CN105008375A - Tetrahydroimidazo[1,5-d][1,4]oxazepine derivative - Google Patents

Tetrahydroimidazo[1,5-d][1,4]oxazepine derivative Download PDF

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CN105008375A
CN105008375A CN201480009750.3A CN201480009750A CN105008375A CN 105008375 A CN105008375 A CN 105008375A CN 201480009750 A CN201480009750 A CN 201480009750A CN 105008375 A CN105008375 A CN 105008375A
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methyl
nitrae
isosorbide
base
phenyl
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CN105008375B (en
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高石守
佐藤信裕
涩口朋之
元木贵史
高桥良典
佐佐木健雄
A·布劳恩顿
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Eisai R&D Management Co Ltd
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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Abstract

A compound represented by general formula (I) [wherein R represents a hydrogen atom, a C1-6 alkyl group or the like; R1 represents a C1-6 alkyl group, a C1-6 alkoxy group or the like; R2 represents a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group or the like; R3 represents a hydrogen atom, a C1-6 alkyl group or the like; and R4 represents a C1-6 alkyl group or the like] or a pharmaceutically acceptable salt thereof, which is an antagonist of mGluR2 and can be used as a therapeutic agent for neurological disorders associated with mGluR2-associated glutamate dysfunction and diseases, such as Alzheimer's disease.

Description

Imidazolidine is [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate also
background of invention
Invention field
The present invention relates to imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate or its pharmaceutically acceptable acid salt of the antagonistic action had for group II metabotropic glutamate receptor.The invention still further relates to and comprise the medicinal compositions of this compound as activeconstituents.
related background art
L-glutamic acid is known be as regulate in mammiferous central nervous system memory, study and etc. Premium Features and the main pungent neurotransmitter that works.Glutamate receptor is probably divided into two types: namely, ionotropic glutamate receptor (iGlu acceptor) and metabotropic glutamate receptor (mGlu acceptor) (see non-patent document 1) with G-protein coupling.
According to their agonist type, these iGlu acceptors are divided into three types, that is, N-methyl-D-aspartate (NMDA) acceptor, alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole propionic acid (AMPA) acceptor and kainate receptors.On the other hand, these mGlu acceptors have 8 kinds of hypotypes (mGluR1 to 8) and are divided into group I (mGluR1 according to needing the signalling system of conjugation and drug characteristic, mGluR5), group II (mGluR2, and group III (mGluR4 mGluR3), mGluR6, mGluR7 and mGluR8).Group II and group III mGluR is mainly expressed as autoreceptor or heteroreceptor at nerve ending, to suppress adenylate cyclase via Gi albumen and to regulate special K +or Ca 2+channel activity (see non-patent document 2).
In these glutamate receptors, antagonist for group II mGluR shows the effect that improves cognitive function in animal model and shows antidepressant effect and angst resistance effect, and therefore, it is suggested that group II mGluR antagonist is effective (see non-patent document 3,4 and 5) as the cognitive function toughener of novelty or antidepressive.
quote inventory
non-patent literature
[non-patent literature 1] Science (" science "), 258,597-603,1992
[non-patent literature 2] Trends Pharmacol.Sci. (" pharmacology trend, science "), 14,13 (1993)
[non-patent literature 3] Neuropharmacol. (" neuropharmacology "), 46 (7), 907-917 (2004)
[non-patent literature 4] Pharmacol.Therapeutics (" pharmacological treatments "), 104 (3), 233-244 (2004)
[non-patent literature 5] Neuropharmacol. (" neuropharmacology "), 66,40-52 (2013)
summary of the invention
An object of the present invention is to provide and a kind of there is imidazolidine [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate for the antagonistic action of group II metabotropic glutamate receptor or its pharmacy acceptable salt, and comprise their medicinal compositions.
The present invention relates to following [1] to [29]:
[1] compound represented by following chemical formula (I) or its pharmaceutical acceptable acid additive salt:
Wherein R is hydrogen atom or optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl, wherein
When R is hydrogen atom,
R 1be chlorine atom, bromine atoms, trifluoromethyl, ethyl, trifluoromethoxy, the methoxyl group be substituted by phenyl, by C 3-8the methoxyl group of cycloalkyl substituted, the oxyethyl group optionally replaced by 1 to 3 fluorine atom or C 3-8cycloalkyloxy,
R 2fluorine atom, chlorine atom, the methyl optionally replaced by 2 to 3 fluorine atoms, the methoxyl group optionally replaced by 1 to 3 fluorine atom or optionally by the oxyethyl group that 1 to 3 fluorine atom replaces,
R 3hydrogen atom or methyl, and
R 4fluorine atom or optionally by the methyl that 1 to 3 fluorine atom replaces, or
When R is optionally by the C of 1 to 3 fluorine atom replacement 1-6during alkyl,
R 1be hydrogen atom, halogen atom, optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl, is optionally selected from fluorine atom and C by 1 to 3 3-8the C that substituting group in cycloalkyl replaces 1-6alkoxyl group, C 3-8cycloalkyloxy, or 4-to 6-unit heterocyclylalkoxy groups,
R 2be hydrogen atom, cyano group, halogen atom, is optionally selected from the C of the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or be optionally selected from fluorine atom, C by 1 to 3 3-8cycloalkyl and 4-to 6-unit Heterocyclylalkyl in substituting group replace C 1-6alkoxyl group,
R 3hydrogen atom or C 1-6alkyl, and
R 4the C being optionally selected from the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or C 1-6alkoxyl group.
[2] compound Gen Ju [1] or its pharmaceutically acceptable acid salt, wherein
R is optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl,
R 1be hydrogen atom, halogen atom, optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl, is optionally selected from fluorine atom and C by 1 to 3 3-8the C that substituting group in cycloalkyl replaces 1-6alkoxyl group, C 3-8cycloalkyloxy, or 4-to 6-unit heterocyclylalkoxy groups,
R 2be hydrogen atom, cyano group, halogen atom, is optionally selected from the C of the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or be optionally selected from fluorine atom, C by 1 to 3 3-8cycloalkyl and 4-to 6-unit Heterocyclylalkyl in substituting group replace C 1-6alkoxyl group,
R 3hydrogen atom or C 1-6alkyl, and
R 4the C being optionally selected from the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or C 1-6alkoxyl group.
[3] compound Gen Ju [2] or its pharmaceutically acceptable acid salt, wherein R is methyl, ethyl, methyl fluoride or difluoromethyl.
[4] compound Gen Ju [3] or its pharmaceutically acceptable acid salt,
Wherein R 1hydrogen atom, fluorine atom, chlorine atom, methyl, methyl fluoride, difluoromethyl, trifluoromethyl, ethyl, 1,1-bis-fluoro ethyl, methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, 2-fluorine oxyethyl group, 2-propoxy-, cyclo propyl methoxy, ring propoxy-or (trimethylene oxide-3-base) oxygen base.
[5] compound Gen Ju [4] or its pharmaceutically acceptable acid salt,
Wherein R 2hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, methyl fluoride, difluoromethyl, trifluoromethyl, methylol, ethyl, methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, 2-fluorine oxyethyl group, 2-propoxy-, cyclo propyl methoxy, cyclobutyl methoxyl group or (tetrahydrochysene-2H-pyrans-4-base) methoxyl group.
[6] compound Gen Ju [5] or its pharmaceutically acceptable acid salt, wherein R 3hydrogen atom or methyl.
[7] compound Gen Ju [6] or its pharmaceutically acceptable acid salt, wherein R 4methyl, methyl fluoride, difluoromethyl, methylol or methoxyl group.
[8] compound Gen Ju [2] or its pharmaceutically acceptable acid salt, wherein
R is optionally by the methyl that 1 to 2 fluorine atom replaces,
R 1hydrogen atom, chlorine atom, the methyl optionally replaced by 1 to 3 fluorine atom, ethyl, optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group or C 3-6cycloalkyloxy,
R 2be cyano group, chlorine atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl or optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group,
R 3hydrogen atom or methyl, and
R 4optionally by the methyl of 1 to 3 fluorine atom replacement.
[9] compound Gen Ju [2] or its pharmaceutically acceptable acid salt, wherein
R is optionally by the methyl that 1 to 2 fluorine atom replaces,
R 1be hydrogen atom, halogen atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl, optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group or C 3-6cycloalkyloxy,
R 2be cyano group, halogen atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl or optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group,
R 3methyl, and
R 4that its condition is optionally by the methyl that 1 to 3 fluorine atom replaces
Work as R 1when being unsubstituted methoxyl group, R 2it not fluorine atom.
[10] a kind of compound or its a kind of pharmaceutically acceptable acid salt of following compound is selected from:
(R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-6-methyl-3-(3-methyl-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-chloro-4-ring propoxyphenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-(methyl fluoride)-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-(methyl fluoride)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, and
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene.
[11] (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[12] (R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine [1,5-d] [1,4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[13] (R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[14] (R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[15] (R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[16] (S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[17] (S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
[18] medicinal compositions, comprises the compound Gen Ju any one of [1] to [17] or pharmaceutically acceptable acid salt, and one or more pharmaceutically acceptable vehicle.
[19] medicinal compositions Gen Ju [18], it is wherein effective disease or symptom for the antagonistic action of group II metabotropic glutamate receptor that this medicinal compositions is used for the treatment of.
[20] medicinal compositions Gen Ju [19], wherein this disease or symptom are alzheimer's diseases.
[21] be used for the treatment of wherein for the method that the antagonistic action of group II metabotropic glutamate receptor is effective disease or symptom, comprise the experimenter by needing it according to the compound of any one of [1] to [17] or pharmaceutically acceptable acid salt.
[22] according to the method be used for the treatment of of [21], wherein this disease or symptom are alzheimer's diseases.
[23] compound Gen Ju any one of [1] to [17] or pharmaceutically acceptable acid salt, for being wherein use in effective disease or symptom for the antagonistic action of group II metabotropic glutamate receptor in treatment.
[24] according to compound or the pharmaceutically acceptable acid salt of [23], wherein this disease or symptom are alzheimer's diseases.
[25] compound Gen Ju any one of [1] to [17] or pharmaceutically acceptable acid salt are producing the purposes in a kind of medicinal compositions, and it is wherein effective disease or symptom for the antagonistic action of group II metabotropic glutamate receptor that this medicinal compositions is used for the treatment of.
[26] purposes Gen Ju [25], wherein this disease or symptom are alzheimer's diseases.
[27] according to the compound according to any one of [1] to [17] or pharmaceutically acceptable acid salt, use for the activeconstituents as a kind of medicinal compositions.
[28] compound Gen Ju [27] or pharmaceutically acceptable acid salt, wherein this medicinal compositions is a kind of being used for the treatment of wherein for the medicinal compositions that the antagonistic action organizing II metabotropic glutamate receptor is effective disease or symptom.
[29] according to compound or the pharmaceutically acceptable acid salt of [27], wherein this disease or symptom are alzheimer's diseases.
advantageous effect of the present invention
Representated by chemical formula (I) compound of the present invention (also refer to as imidazolidine also [1 hereinafter, 5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate) or its pharmaceutically acceptable acid salt show antagonistic action for group II metabotropic glutamate receptor.Therefore, imidazolidine of the present invention also [1,5-d] [1,4] oxygen azepine derivate or its a kind of pharmaceutically acceptable acid salt have the potential use as a kind of therapeutical agent, this treatment and for the disease that wherein effectively acts on for the antagonistic action of group II metabotropic glutamate receptor or symptom, this disease or symptom are such as alzheimer's diseases.
the explanation of preferred embodiment
Hereinafter, as used herein symbol, term and etc. implication will be explained and be the invention will now be more particularly described.
At this, the structural formula of compound can represent given isomers for convenience's sake, but compound of the present invention comprises isomer, the all geometrical isomers such as structurally formed from this compound, optical isomer, steric isomer and tautomer based on asymmetric carbon and its heterogeneous mixture, and this compound is not limited to given chemical formula for convenience's sake, but can be any one in these isomer and mixture.Therefore, compound of the present invention can have unsymmetrical carbon in the molecule thereof and can exist as optically active material or racemic form, but the present invention is not limited thereto but it comprises all situations.By accident, the mixture of any one isomers, racemic compound and isomers can show the activity stronger than other isomerss.In addition, can there is crystal polymorphism, this does not also limit the present invention, and this compound can be any single crystal or its mixture, and can be a kind of hydrate or a kind of solvate together with a kind of anhydride, all these are included in the scope of this claims.
The present invention includes the isotope-labeled compound with chemical formula (I).This isotope-labeled compound is equivalent with the compound with chemical formula (I), exception part to be one or more atom had one or more atoms of being different from those atomic mass or the total mass number usually found at occurring in nature substitute.The isotopic example that can be merged into compound of the present invention comprises following isotropic substance: hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, phosphorus, sulphur and iodine, such as 2h, 3h, 11c, 14c, 13n, 15o, 18f, 32p, 35s, 123i and 125i.
Comprise any above-mentioned isotropic substance and/or another isotopic compound of the present invention, and its pharmaceutically acceptable derivates (such as salt) falls within the scope of this claims.(e.g., isotope-labeled compound of the present invention, such as, wherein contain radio isotope 3h and/or 14c) those, can have the tissue distribution for medicine and/or matrix to measure.Isotropic substance 3h and 14c is considered to useful, because these isotropic substances are easy to preparation and determination methods.Isotropic substance 11c and 18f has been considered to for PET (positron emission computerized tomography), isotropic substance 125i has been considered to for SPECT (Single Photon Emission Computed tomoscan), and all these isotropic substances have for Brian Imaging.Due to the metabolic stability that it is higher, with higher isotope as 2h carries out substituting the advantage causing some types in treatment kind, as the prolongation of Half-life in vivo or the minimizing of required dosage, and is therefore considered to be useful in a given case.The isotope-labeled compound with chemical formula (I) of the present invention can be replaced nonisotopically labelled reagent by using conventional isotope-labeled reagent and similarly be prepared by the program of carrying out disclosing in scheme described below and/or example.
At this, " halogen atom " means fluorine atom, chlorine atom, bromine atoms, atomic iodine and analogue, and is preferably fluorine atom or chlorine atom.
" C 1-6alkyl " mean the straight or branched alkyl with 1 to 6 carbon atom, and concrete example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 1-methyl-propyl, 1, 2-dimethyl propyl, 1-ethyl propyl, 1-methyl-2-ethyl propyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-thmethylpropyl, 1-methyl butyl, 2-methyl butyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 2-ethyl-butyl, 1, 3-dimethylbutyl, 2-methyl amyl and 3-methyl amyl, and preferred example comprises methyl, ethyl and n-propyl.
" C 1-6alkoxyl group " mean oxygen base and be bonded to " C 1-6alkyl ", and specific examples comprises methoxyl group, oxyethyl group, 1-propoxy-, 2-propoxy-, 2-methyl isophthalic acid-propoxy-, 2-methyl-2-propoxy-, 1-butoxy, 2-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-1-butene oxygen base, 3-methyl isophthalic acid-butoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 2, 2-dimethyl-1-propoxy-, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 2-methyl-1-pentene oxygen base, 3-methyl-1-pentene oxygen base, 4-methyl-1-pentene oxygen base, 2-methyl-2-pentyloxy, 3-methyl-2-pentyloxy, 4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy, 2, 3-dimethyl-1-butoxy, 3, 3-dimethyl-1-butoxy, 2, 2-dimethyl-1-butoxy, 2-ethyl-1-butoxy, 3, 3-dimethyl-2-butoxy and 2, 3-dimethyl-2-butoxy, and preferred example comprises methoxyl group, oxyethyl group and 1-propoxy-.
" C 3-8cycloalkyl " be meant to the cycloalkyl with 3 to 8 carbon atoms, and specific examples comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
" optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl " mean unsubstituted " C 1- 6alkyl " or the wherein " C that is replaced by fluorine atoms of 1 to 3 hydrogen atom 1-6alkyl ".By the C that 1 to 3 fluorine atom replaces 1-6the specific examples of alkyl comprises methyl fluoride, 1-fluoro ethyl, 2-fluoro ethyl, 3-fluoropropyl, difluoromethyl, 1,1-bis-fluoro ethyl, 2,2-bis-fluoro ethyls, trifluoromethyl and 2,2,2-trifluoroethyl.
" be optionally selected from fluorine atom and C by 1 to 3 3-8the C that substituting group in cycloalkyl replaces 1-6alkoxyl group " mean unsubstituted " C 1-6alkoxyl group " or wherein 1 to 3 hydrogen atom by fluorine atom or C 3-8" the C of cycloalkyl substituted 1-6alkoxyl group ".By the C that one or more fluorine atom replaces 1-6the specific examples of alkoxyl group comprises fluorine methoxyl group, 1-fluorine oxyethyl group, 2-fluorine oxyethyl group, 3-fluorine propoxy-, difluoro-methoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxies, trifluoromethoxy and 2,2,2-trifluoro ethoxy.By C 3-8the C of cycloalkyl substituted 1-6the specific examples of alkoxyl group comprises cyclo propyl methoxy, cyclobutyl methoxyl group, cyclopentylmethoxy, cyclohexyl methoxy, cyclopropylethoxy, cyclobutyl oxyethyl group, cyclopentyl oxyethyl group and cyclohexylethoxy radical.
" C 3-8cycloalkyloxy " the oxygen base that is meant to be bonded to " C 3-8cycloalkyl " and specific examples comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base and ring octyloxy.
" 4-to 6-unit Heterocyclylalkyl " means heteroatomic 4-to the 6-unit cyclic group comprising one or more nitrogen, oxygen, sulphur and analogue, and specific examples comprises 3-azetidinyl, 1-methyl-3-azetidinyl, 3-pyrrolidyl, 1-methyl-3-pyrrolidyl, 1-methyl-3-piperidyl, 1-methyl-4-piperidyl, 3-oxetanyl, 3-tetrahydrofuran base, 3-THP trtrahydropyranyl, 4-THP trtrahydropyranyl, 3-tetrahydro-thienyl and 4-tetrahydro thiapyran base.
" 4-to 6-unit heterocyclylalkoxy groups " means oxygen base and is bonded to " 4-to 6-unit Heterocyclylalkyl ", and specific examples comprises 3-azetidinyl oxygen base, 1-methyl-3-azetidinyl oxygen base, 3-pyrrolidyl oxygen base, 1-methyl-3-pyrrolidyl oxygen base, 1-methyl-3-piperidyl oxygen base, 1-methyl-4-piperidyl oxygen base, 3-oxetanyl oxygen base, 3-tetrahydrofuran base oxygen base, 3-THP trtrahydropyranyl oxygen base, 4-THP trtrahydropyranyl oxygen base, 3-tetrahydro-thienyl oxygen base and 4-tetrahydro thiapyran base oxygen base.
The imidazolidine with chemical formula (I) of the present invention also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate can be in pharmaceutically acceptable acid addition salt form thereof.The specific examples of pharmaceutically acceptable acid salt comprises: inorganic acid salt (such as, vitriol, nitrate, perchlorate, phosphoric acid salt, carbonate, supercarbonate, hydrofluoride, hydrochloride, hydrobromate, hydriodate); Organic carboxylate (such as, acetate, oxalate, maleate, tartrate, fumarate, Citrate trianion); Organic sulfonate (such as, mesylate, fluoroform sulphonate, esilate, benzene sulfonate, tosylate, camsilate); Amino acid salts (such as, aspartate, glutaminate).
Embodiments of the invention comprise the compound or its pharmaceutically acceptable acid salt that are represented by following chemical formula (I):
Wherein R, R 1, R 2, R 3and R 4represent as in above [1], definition is identical.
The preferred embodiment of the invention provides imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate or its pharmaceutically acceptable acid salt, wherein when R is the hydrogen atom in chemical formula (I), and R 1be chlorine atom, bromine atoms, trifluoromethyl, ethyl, trifluoromethoxy, the methyl be substituted by phenyl, by C 3-8the methoxyl group of cycloalkyl substituted, the oxyethyl group optionally replaced by 1 to 3 fluorine atom or C 3-8cycloalkyloxy; R 2fluorine atom, chlorine atom, the methyl optionally replaced by 2 to 3 fluorine atoms, the methoxyl group optionally replaced by 1 to 3 fluorine atom or optionally by oxyethyl group that 1 to 3 fluorine atom replaces; R 3hydrogen atom or methyl; And R 4it is fluorine atom or optionally by methyl that 1 to 3 fluorine atom replaces.
Another preferred embodiment of the present invention is imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate or its pharmaceutically acceptable acid salt, wherein when R is optionally by the C of 1 to 3 fluorine atom replacement in chemical formula (I) 1-6during alkyl, R 1be hydrogen atom, halogen atom, optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl, is optionally selected from fluorine atom and C by 1 to 3 3-8the C that substituting group in cycloalkyl replaces 1-6alkoxyl group, C 3-8cycloalkyloxy, or 4-to 6-unit heterocyclylalkoxy groups; R 2be hydrogen atom, cyano group, halogen atom, is optionally selected from the C of the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or be optionally selected from fluorine atom, C by 1 to 3 3-8cycloalkyl and 4-to 6-unit Heterocyclylalkyl in substituting group replace C 1-6alkoxyl group; R 3hydrogen atom or C 1-6alkyl; And R 4the C being optionally selected from the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or C 1-6alkoxyl group.
In chemical formula (I), R is preferably methyl, ethyl, methyl fluoride or difluoromethyl; R 1preferably hydrogen atom, fluorine atom, chlorine atom, methyl, methyl fluoride, difluoromethyl, trifluoromethyl, ethyl, 1,1-bis-fluoro ethyl, methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, 2-fluorine oxyethyl group, 2-propoxy-, cyclo propyl methoxy, ring propoxy-or (trimethylene oxide-3-base) oxygen base; R 2preferably hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, methyl fluoride, difluoromethyl, trifluoromethyl, methylol, ethyl, methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, 2-fluorine oxyethyl group, 2-propoxy-, cyclo propyl methoxy, cyclobutyl methoxyl group or (tetrahydrochysene-2H-pyrans-4-base) methoxyl group; R 3preferably hydrogen atom or methyl; And R 4preferably methyl, methyl fluoride, difluoromethyl, methylol or methoxyl group.
In chemical formula (I), R, R 1, R 2, R 3and R 4preferred combination is as following: R is optionally by the methyl of 1 to 2 fluorine atom replacement; R 1be hydrogen atom, halogen atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl, optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group or C 3-6cycloalkyloxy; R 2be cyano group, halogen atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl or optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group; R 3it is methyl; R 4that its condition works as R optionally by the methyl that 1 to 3 fluorine atom replaces 1when being unsubstituted methoxyl group, R 2it not fluorine atom.
Particularly, according to imidazolidine of the present invention also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate or its pharmaceutically acceptable acid salt be preferably selected from following compound:
(R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-6-methyl-3-(3-methyl-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-chloro-4-ring propoxyphenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-(methyl fluoride)-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-(methyl fluoride)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, or
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene.
Imidazolidine also [1,5-d] [1,4] the preferred example of oxygen azepine derivate or its a kind of pharmaceutically acceptable acid salt is (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt,
(R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt,
(R)-3-(4-(difluoroethoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt, and
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, representated by following chemical formula:
Or its a kind of pharmaceutically acceptable acid salt.
Next, use description to produce representated by chemical formula of the present invention (I) compound (hereinafter referred to as compound (I); Like other compounds representated by other chemical formulas, use this to express) or the method for its pharmaceutically acceptable acid salt.
Scheme 1
Chemical formula (I) (wherein R, R 1, R 2, R 3and R 4representative with such as defined above identical) can be prepared according to scheme 1, by such as compound (II) suzuki reaction with compound (III).Compound (II) and compound (III) heating by under the existence of such as a kind of palladium catalyst and a kind of alkali, can carry out, add phosphorus part if necessary by suzuki reaction in a kind of solvent.As palladium catalyst, such as tetrakis triphenylphosphine palladium (0), acid chloride (II), Pd can be used 2dBA 3or (A-taPhos) 2pdCl 2.As alkali, such as, can use potassiumphosphate, sodium hydroxide, potassium hydroxide, hydrated barta, sodium carbonate or cesium carbonate.In addition, as phosphorus part, such as triphenylphosphine, butyl two (1-adamantyl) phosphine or 2-dicyclohexylphosphontetrafluoroborate-2' can be used, 4', 6'-tri isopropyl biphenyl.The solvent used in the reaction is not particularly limited, as long as it is a kind of inert solvent, and such as can use THF, DME, DMF, Isosorbide-5-Nitrae-diox, water or these mixed solvent.This reaction is accelerated by heating, but usually carries out from room temperature to the reflux temperature of this solution in temperature range, and can adopt microwave heating as occasion needs.
Work as R 4that, such as, during methylol, this compound can also from wherein R 4being the production of chemicals of methyl, by using mCPBA or analogue to carry out oxidizing reaction, using diacetyl oxide or analogue to carry out rearrangement reaction and basic hydrolysis.
Work as R 2that, such as, during methylol, this compound can also be generate by the deprotection of the respective compound of MOM or analogue protection by wherein methylol.
Work as R 1or R 2be; such as during alkoxyl group; this compound can also pass through in a kind of solvent (such as DMF or THF) and under the existence of a kind of alkali (such as salt of wormwood or cesium carbonate), carry out alkylation generation with alkyl bromide, alkyl iodide, alkyl triflate or analogue to a kind of compound (this compound is obtained by a kind of corresponding alkylol cpd protected by MOM, benzyl, methyl or analogue of deprotection).Usually this reaction is carried out from room temperature to the reflux temperature of this solution in temperature range.
Work as R 4or R 2that, such as during methyl fluoride, this compound can by generating the fluorination of methylol and DAST, BAST or analogue.
Scheme 2
Compound (II) (wherein R, R 1and R 2representative with such as defined above identical) can be prepared according to scheme 2, by the decarboxylation bromination of the Ester hydrolysis of such as compound (IV) and the compound (V) of generation.The solvent used in the esterolysis of compound (IV) is not particularly limited, as long as it is a kind of inert solvent, and such as can use methyl alcohol, ethanol, THF or its water-containing solvent.In addition, as alkali, such as, sodium hydroxide or potassium hydroxide can be used.This reaction by accelerating, but is carried out from room temperature to the reflux temperature of this solution in temperature range usually.The solvent used in the decarboxylation bromination of compound (V) is not particularly limited, and such as can use the mixed solvent of DMF, ethanol or DMF and ethanol.In addition, bromine source can be such as NBS.If salt of wormwood or analogue use as alkali, this reaction is accelerated, and this reaction is carried out from room temperature in temperature range usually to the reflux temperature of this solution.
Work as R 1or R 2be; such as during alkoxyl group; this compound can also pass through in a kind of solvent (such as DMF or THF) and under the existence of a kind of alkali (such as salt of wormwood or cesium carbonate), carry out alkylation generation with alkyl bromide, alkyl iodide, alkyl triflate or analogue to a kind of compound (this compound is obtained by a kind of corresponding alkylol cpd protected by MOM, benzyl, methyl or analogue of deprotection).Usually this reaction is carried out from room temperature to the reflux temperature of this solution in temperature range.
Scheme 3
Compound (IV) (wherein R, R 1and R 2representative with such as defined above identical) can be prepared according to scheme 3, by such as compound (VI) and compound (VII) being carried out condensation reaction and the compound (VIII) using alkaline purification to produce.The solvent used in the condensation reaction of compound (VI) and (VII) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene, THF, DME or these mixed solvent.This reaction is accelerated by heating, but usually carries out from room temperature to the reflux temperature of this solution in temperature range, and can adopt microwave heating as occasion needs.Being not particularly limited with the solvent used in alkaline purification compound (VIII), as long as it is a kind of inert solvent, and such as methyl alcohol can be used.This alkali can be such as sodium methylate.This reaction is accelerated by heating, but usually carries out from room temperature to the reflux temperature of this solution in temperature range, and can adopt microwave heating as occasion needs.
Work as R 1or R 2be; such as during alkoxyl group; this compound can also pass through in a kind of solvent (such as DMF or THF) and under the existence of a kind of alkali (such as salt of wormwood or cesium carbonate), carry out alkylation generation with alkyl bromide, alkyl iodide, alkyl triflate or analogue to a kind of compound (this compound is obtained by a kind of corresponding alkylol cpd protected by MOM, benzyl, methyl or analogue of deprotection).Usually this reaction is carried out from room temperature to the reflux temperature of this solution in temperature range.
Scheme 4
Compound (VI) (wherein R 1and R 2representative with such as defined above identical) can be prepared according to scheme 4, by the compound (X) of the sour chlorization of such as compound (IX), generation and compound (XI) amidation in the basic conditions and the cyclic action of compound (XII) that produces.The solvent used in the sour chlorization of compound (IX) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene or DCM.In addition, oxalyl chloride and thionyl chloride can be used for this reaction, and this reaction is accelerated by adding DMF.This reaction by accelerating, but is carried out from ice-cooled temperature to the reflux temperature of this solution in temperature range usually.The solvent used in the amidation of compound (X) and (XI) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene, THF, DCM or these mixed solvent.In addition, as alkali, such as, sodium hydroxide or potassium hydroxide can be used.Usually this reaction is carried out from ice-cooled temperature to the reflux temperature of this solution in temperature range.The solvent used in the cyclic action of compound (XII) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene or THF.In addition, methyl-chloroformate, isopropyl chlorocarbonate, DCC or analogue may be used for cyclic action.Usually this reaction is carried out from-78 DEG C to the reflux temperature of this solution in temperature range.
Scheme 5
Chemical formula (IV) (wherein R, R 1and R 2representative with such as defined above identical) also can be prepared according to scheme 5, by such as compound (XIII) (wherein X the is halogen) suzuki reaction with compound (XIV).Compound (XIII) and compound (XIV) heating by under the existence of such as a kind of palladium catalyst and a kind of alkali, can carry out, add phosphorus part if necessary by suzuki reaction in a kind of solvent.As palladium catalyst, such as tetrakis triphenylphosphine palladium (0), acid chloride (II) salt, Pd can be used 2dBA 3or (A-taPhos) 2pdCl 2.As alkali, such as, can use potassiumphosphate, sodium hydroxide, potassium hydroxide, hydrated barta, sodium carbonate or cesium carbonate.In addition, as phosphorus part, such as triphenylphosphine, butyl two (1-adamantyl) phosphine or 2-dicyclohexylphosphontetrafluoroborate-2' can be used, 4', 6'-tri isopropyl biphenyl.The solvent used in the reaction is not particularly limited, as long as it is a kind of inert solvent, and such as can use THF, DME, DMF, Isosorbide-5-Nitrae-diox or benzene.This reaction is accelerated by heating, but usually carries out from room temperature to the reflux temperature of this solution in temperature range, and can adopt microwave heating as occasion needs.
Scheme 6
Compound (XIII) (wherein R be with such as defined above identical and X is halogen) can be prepared according to scheme 6, by the condensation reaction of such as compound (VII) with compound (XV), the Hoffmann rearrangement reaction of the compound (XVI) produced, and the halogenation of the compound (XVII) produced.The solvent used in the condensation reaction of compound (VII) and (XV) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene, THF, DMF, DME or these mixed solvent.This reaction is accelerated by heating, but usually carries out from room temperature to the reflux temperature of this solution in temperature range, and can adopt microwave heating as occasion needs.The solvent used in the rearrangement reaction of compound (XVI) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene, THF, DME or these mixed solvent.In addition, iodobenzene diacetate or analogue can use in the reaction.Usually this reaction is carried out from room temperature to the reflux temperature of this solution in temperature range.The solvent used in the halogenation of compound (XVII) is not particularly limited, as long as it is a kind of inert solvent, and such as can use toluene.In addition, phosphoryl chloride or phosphorus oxybromide can use in the reaction.This reaction by accelerating, but is carried out from room temperature to the reflux temperature of this solution in temperature range usually.
Scheme 7
Compound (VII) (wherein R be with such as defined above identical) can be prepared according to scheme 7, by such as four steps, 1 of compound (XVIII) and compound (XIX), 4-addition reaction, compound (XX) alcoholysis in acid condition produced, compound (XXI) cyclic action in the basic conditions produced, and the O-alkylation producing compound (XXII).In the Isosorbide-5-Nitrae-addition reaction of compound (XVIII), this compound (XIX) can be used as solvent.As alkali, DBU, TEA, DIPEA or analogue can be used.Usually this reaction is carried out from ice-cooled temperature to the reflux temperature of this solution in temperature range.The solvent used in the alcoholysis of compound (XX) is not particularly limited, as long as it is a kind of inert solvent, and such as can use Isosorbide-5-Nitrae-diox.As acid, hydrogenchloride or analogue can be used.This reaction by accelerating, but is carried out from room temperature to the reflux temperature of this solution in temperature range usually.The solvent used in the cyclic action of compound (XXI) is not particularly limited, as long as it is a kind of inert solvent, and such as can use methyl alcohol or analogue.As alkali, DBU, TEA, salt of wormwood or cesium carbonate can be used.This reaction by accelerating, but is carried out from room temperature to the reflux temperature of this solution in temperature range usually.The solvent used in the O-alkylating of compound (XXII) is not particularly limited, as long as it is a kind of inert solvent, and such as can use DCM or toluene.As alkylating agent, trimethylammonium oxygen Tetrafluoroboric acid, methyl-sulfate or analogue can be used.Usually this reaction is carried out from ice-cooled temperature to the reflux temperature of this solution in temperature range.
Scheme 8
Compound (XXII) (wherein R be with such as defined above identical) can be prepared according to scheme 8; by such as four steps; the dehydrating condensation of compound (XXIII) and compound (XXIV); compound (XXV) cyclic action in acid condition produced; the hydrogenization of the compound (XXVI) produced, and the deprotection of the compound (XXVII) produced.The solvent used in the dehydrating condensation of compound (XXIII) with compound (XXIV) is not particularly limited, as long as it is a kind of inert solvent, and such as can use THF, DMF or DCM.In addition, condensing agent can be DCC, EDC, HOBt, HATU, HBTU or these any combination.In addition, DIPEA, TEA or analogue can be used as additive in the reaction.Usually this reaction is carried out from ice-cooled temperature to the reflux temperature of this solution in temperature range.The solvent used in the cyclic action of compound (XXV) is not particularly limited, as long as it is a kind of inert solvent, and such as can use THF, acetonitrile, toluene or dimethylbenzene.In addition, acid can be, such as, PTS or PPTS.This reaction by accelerating, but is carried out from room temperature to the reflux temperature of this solution in temperature range usually.The solvent used in the hydrogenization of compound (XXVI) is not particularly limited, as long as it is a kind of inert solvent, and such as can use methyl alcohol, ethanol or THF.As catalyzer, palladium/carbon, palladium hydroxide/carbon, platinum oxide or analogue can be used.Usually this reaction is carried out from room temperature to the reflux temperature of this solution in temperature range.The deprotection of compound (XXVII) can carry out in such as a kind of solvent (as TFA).As additive, such as scavenging agent (as triethyl silicane) can be used.This reaction by accelerating, but is carried out from room temperature to the reflux temperature of this solution in temperature range usually.
As occasion demand can by ordinary method by the compound of the present invention (I) that so obtains for entering pharmacy acceptable salt.This preparation method can be the appropriately combined of the method for such as conventional employing in synthetic organic chemistry field.The specific examples of the method comprises and carries out neutralization titration with a kind of acid solution to the solution of the compounds of this invention of free form.In addition, needed for occasion, compound of the present invention (I) can be changed into a kind of solvate by known solvate forming reactions.
Up to the present, describe the representative example of the method for the production of compound (I), and the material compound used in the production method for compound (I) and different reagent can be in the form of salt or hydrate, and according to the parent material used, there are solvent to be used and analogue and different, and be therefore not particularly limited, as long as this reaction is not suppressed.Have solvent to be used different according to parent material, reagent and analogue, and needless to say, be not particularly limited, if it does not suppress these reaction and they dissolve initial substance to a certain extent.When this compound (I) obtains in a free form, according to conventional methods, the salt form that this compound (I) can be formed can be translated into.Similarly, when this compound (I) be obtain with the salt form of this compound (I) time, the free form of this compound (I) can be translated into by ordinary method.In addition, can the different isomer of this compound (I) that obtains of purifying (such as, geometrical isomer, optically active isomer, steric isomer and tautomer based on unsymmetrical carbon) and can by using common separation method, such as recrystallization, diastereomeric salt formation method, enzymatic resolution method and different chromatography type (such as, thin layer chromatography, column chromatography and gas chromatography) are separated it.
Term " composition " spawn that comprises the product containing the special component being in concrete content and directly or indirectly prepared by the combination of the concrete composition of concrete content as used herein.This type of term about medicinal compositions is used to be intended to comprise: to comprise a kind of activeconstituents and a kind of product forming the non-active ingredient of carrier; And by the combination of two or more compositions any, complexing or polymerization, or the dissociating of one or more compositions, the reaction of another kind of type or all products of interacting and preparing directly or indirectly.Correspondingly, medicinal compositions of the present invention comprise by by imidazolidine of the present invention also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate mix with any pharmaceutically acceptable carrier all compositions be prepared.Term " pharmaceutically acceptable " means carrier, other compositions of thinner or vehicle and preparation must be compatible and to take said composition those to as if harmless.
Compound of the present invention mainly has the ability as being bonded to group II metabotropic glutamate receptor, 100nM or less IC50 value, and preferably has 30nM or less IC50 value, and more preferably 10nM or less.
Imidazolidine of the present invention also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate or its pharmaceutically acceptable acid salt has the antagonistic action for group II metabotropic glutamate receptor.Correspondingly, it is applicable as the therapeutical agent of the disease wherein effectively worked for the antagonistic action of group II metabotropic glutamate receptor.The example of the disease wherein effectively worked for the antagonistic action of group II metabotropic glutamate receptor comprises alzheimer's disease.
Imidazolidine of the present invention also [[1,5-d] [1,4] oxygen azepine derivate or its pharmaceutically acceptable acid salt can be prepared by ordinary method, and this formulation can be such as oral formulation (as tablet, granule, pulvis, capsule or syrup), injection preparation (for intravenous administration, intramuscular adminstration, subcutaneous administration, Intraperitoneal medication or similar etc.) or external application preparation (as percutaneous medicament (comprising ointment, paster and analogue), eye drops, nose drops or suppository).
For production oral administration solid preparation, can to imidazolidine of the present invention also [1 if cross needs, 5-d] [1,4] add vehicle, tackiness agent, disintegrating agent, lubricant, tinting material and analogue in oxygen azepine derivate or its pharmaceutically acceptable acid salt, and by conventional method, the preparation of the mixture of generation is become tablet, granule, pulvis or capsule.In addition, if needed, tablet, granule, pulvis or capsule can have film by dressing.
The example of vehicle comprises lactose, W-Gum and crystalline cellulose, the example of tackiness agent comprises hydroxypropylcellulose and Vltra tears, the example of disintegrating agent comprises calcium carboxymethylcellulose and croscarmellose sodium, the example of lubricant comprises Magnesium Stearate and calcium stearate, the example of tinting material comprises titanium oxide, and film coating agent comprises hydroxypropylcellulose, Vltra tears and methylcellulose gum, and self-evidently these compositions are not limited to aforementioned example.
The solid formulation of such as tablet, capsule, granule or pulvis can with usually by weight 0.001% to 99.5%, preferably by weight 0.001% to 90% and similar etc. content comprise imidazolidine of the present invention also [1,5-d] [1,4] oxygen azepine derivate, its a kind of pharmacy acceptable salt, or its solvate.
For production injection preparation (for intravenous administration, intramuscular adminstration, subcutaneous administration, Intraperitoneal medication or similar administration), can to imidazolidine of the present invention also [1 if cross needs, 5-d] [1,4] add pH adjusting agent, buffer reagent, suspension agent, solubilizing agent, antioxidant, sanitas (a kind of antiseptic-germicide), a kind of tonicity contributor and analogue in oxygen azepine derivate or its pharmaceutically acceptable acid salt, and by conventional method, the preparation of the mixture of generation is become injection preparation.In addition, can by resultant freeze-drying to use as the lyophilized products needing to be dissolved before the use.
The example of pH adjusting agent and buffer reagent comprises organic acid, mineral acid and/or its salt, the example of suspension agent comprises methylcellulose gum, polysorbate80 and Xylo-Mucine, the example of solubilizing agent comprises polysorbate80 and Tween 20, the example of antioxidant comprises alpha-tocopherol, the example of sanitas comprises methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate, and the example of tension regulator comprises glucose, sodium-chlor and N.F,USP MANNITOL, and self-evidently these compositions are not limited to above-mentioned example.
This type of injection preparation can with usually by weight 0.000001% to 99.5%, preferably by weight 0.000001% to 90% and similar etc. content comprise imidazolidine of the present invention also [1,5-d] [1,4] oxygen azepine derivate, its a kind of pharmacy acceptable salt, or its solvate.
For production external application preparation, can to imidazolidine of the present invention also [1 if cross needs, 5-d] [1,4] base mateiral is added in oxygen azepine derivate or its pharmaceutically acceptable acid salt, such as, by sanitas described above, stablizer, pH adjusting agent, antioxidant, add further wherein with tinting material and analogue, and by ordinary method, the preparation of the mixture of generation is become, such as, the medicine (such as ointment or patch) of percutaneous absorbtion, eye drops, nose drops or suppository.
As by by the base mateiral used, can use through being usually used in, such as, the differing materials of medicine, class-medicine and makeup.The specific examples of this type of material comprises animal oil or vegetables oil, mineral oil, ester oil, wax class, emulsifying agent, higher alcohols, lipid acid, silicone oil, tensio-active agent, phosphatide, alcohol, polyvalent alcohol, water-soluble polymers, clay mineral and purifies waste water.
This type of external application preparation can with usually by weight 0.000001% to 99.5%, preferably by weight 0.000001% to 90% and similar etc. content comprise imidazolidine of the present invention also [1,5-d] [1,4] oxygen azepine derivate, its a kind of pharmacy acceptable salt, or its solvate.
Imidazolidine of the present invention also [1, 5-d] [1, 4] dosage of oxygen azepine derivate or its pharmaceutically acceptable acid salt depends on the level of symptom severity, patient age, sex and weight, form of medication and salt kind, the concrete kind of disease and etc., and in adult patients, once a day or respectively administration several times, with the qf oral administration dosage of about 30 μ g to 10g usually, preferably 100 μ g to 5g and more preferably 100 μ g to 1g, or with the drug administration by injection dosage of about 30 μ g to 1g usually, preferably 100 μ g to 500mg, and more preferably 100 μ g to 300mg.
Compound of the present invention can use as the chemical probe for catching the target protein with bioactive low-molecular weight compound.Particularly, according at J.Mass Spectrum.Soc.Jpn. (" Japanese mass-spectrometry can magazine ") Vol.51, No.5,2003, p.492-498; Method described in WO 2007/139149 grade, by labelling groups, connector or analogue being incorporated in the part except the necessary structure division of this compound of activity expression, can be affinity chromatography probe, photoaffinity probe or analogue by converting compounds of the present invention.
Example for this labelling groups, connector or the analogue that use in such chemical probe comprises the group belonging to and describe in following group (1) to (5):
(1) protein labeling group, if photoaffinity labeling group (as benzoyl, benzophenone base, azido-, carbonyl azide base, two '-aziridinos, ketenes base, diazo and nitro) and chemical affinity groups are (as ketone group, one of them alpha-carbon atom is by halogen atom, formamyl, ester group, alkylthio, α, Michael (Michael) acceptor of alpha, beta-unsaturated ketone, ester or analogue replaces, and Oxyranyle);
(2) cleavable connector, as-S-S-,-O-Si-O-, monose (as glucosyl group and galactosyl) or disaccharides (as lactose) and the oligopeptides connector by enzymatic reaction cracking;
(3) adopt and catch (fishing) marker groups, as vitamin H and 3-(fluoro-5, the 7-dimethyl-4H-3a of 4,4-bis-, 4a-diaza-4-boron mix-s-Dicyclopentadiene (DCPD) acene (indacen)-3-base) propionyl;
(4) radiolabeled group as 125i, 32p, 3h and 14c; Fluorescence marker groups is as fluorescein, rhodamine, dansyl, Umbelliferone, 7-nitro furan a word used for translation base and 3-(fluoro-5, the 7-dimethyl-4H-3a of 4,4-bis-, 4a-diaza-4-boron mix-s-Dicyclopentadiene (DCPD) acene-3-base) propionyl; Chemiluminescent groups as sharp in Rumi takes (lumiferin) and luminol,3-aminophthalic acid cyclic hydrazide (luminol); And the marker that can detect, comprise heavy metal ion as lanthanide metal ion and radium ion; And
(5) allow to be attached to solid phase carrier as the group on granulated glass sphere, glass bed, microwell plate, sepharose 4B, agarose bed, polystyrene bead, polystyrene bed, nylon beads and nylon bed.
According to the method described in above-mentioned publication and analogue by the labelling groups or analogue that are selected from above-mentioned group (1) to (5) being incorporated into the probe of preparation in compound of the present invention, can be used as the chemical probe of identification marking albumen, this labelled protein is useful to the potential drug target spot or analogue of studying novelty.
Hereinafter, in more detail the present invention is described with reference to example, production instance and test case.But the present invention is not limited to them.In addition, the abbreviation used in these examples will be the conventional abbreviation that those of ordinary skill in the art knows, and some abbreviations will in following description.
(A-taPhos) 2pdCl 2: two (two-tert-butyl (4-dimethylaminophenyl) phosphine) dichloro palladium (II)
BAST: two (2-methoxy ethyl) amino sulfur trifluoride
Bn: benzyl
Boc: uncle-butoxy carbonyl
CSA: camphorsulfonic acid
DAST: diethylaminosulfur trifluoride
DBN:1.5-diazabicylo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene
DBU:1,8-diazabicylo [5.4.0] 11-7-alkene
DCC:1,3-dicyclohexylcarbodiimide
DCE:1,2-ethylene dichloride
DCM: methylene dichloride
DIPEA: diisopropylethylamine
DME: glycol dimethyl ether
DMF:N, dinethylformamide
DMPI: Dai Si-Martin oxygenant (Dess-Martin Periodinane)
DMSO: methyl-sulphoxide
EDC:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
HATU:O-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea hexafluorophosphate
HATU:O-benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate
HFIP:1,1,1,3,3,3-hexafluoro-2-propyl alcohol
HOBT:1-hydroxybenzotriazole
MCPBA:3-chlorine peroxybenzoic acid
MOM: methoxymethoxy
N-: just
NBS:N-bromo-succinimide
NMM:N-methylmorpholine
Pd (dppf) Cl 2cH 2cl 2: (two (diphenylphosphino) ferrocene-dichloro palladium-dichloromethane complex of 1,1'-
Pd 2dBA 3: three (dibenzylideneacetone) two palladium
PPTS: pyridinium p-toluenesulfonate
PTS: tosic acid
Tert-: uncle
TBAF: tetrabutylammonium
TBS: tert-butyl dimetylsilyl
TBSCl: tert-butyl dimethylsilylchloride
TBME: tert-butyl methyl ether
TEA: triethylamine
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
Ts: p-toluenesulfonyl
1h-NMR: proton NMR spectral analytical method
Chemical shift in proton NMR spectrum is by carrying out recording relative to δ (ppm) unit of tetramethylsilane and coupling constant carries out record with Herz (Hz) unit.Pattern comprises, s; Unimodal, d; Bimodal, t; Three peaks, q; Four peaks, br; Broad peak, and sep; Seven peaks.
The term " room temperature " described in following instance and production instance represents usually in about 10 DEG C of temperature to 35 DEG C of scopes.Unless otherwise indicated, symbol " % " represents percentage ratio by weight.
The chemical name of the compound in example and production instance determines based on the chemical structure of their references " E-notebook (E-Notebook) " 12 editions (platinum Elmer Co., Ltd (PerkinElmer Inc.)).
Production instance 1
(R) synthesis of-5-methoxyl group-2-methyl-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
(1) (R)-1-((2,4-dimethoxy-benzyl) is amino) propan-2-olsynthesis
At room temperature, to (R)-(-)-1-amino-2-propyl alcohol (CAS numbering 2799-16-8; 24.0g, 320mmol) and the solution of acetic acid (40.2mL, 703mmol) in THF (440mL) in add 2,4-dimethoxy benzaldehyde (CAS numbering 613-45-65; 55.8g, 336mmol), and this mixture is at room temperature stirred 1 hour.At room temperature in this reaction liquid, add triacetoxyl group sodium borohydride (102g, 479mmol), and this mixture is stirred 18 hours.After reaction, this solvent is under reduced pressure concentrated.The aqueous sodium hydroxide solution (100mL) of 5N and ethyl acetate (500mL) are added to and generates in resistates to be separated this organic layer.Chloroform (300mL) is added to the water layer of this generation to be separated this organic layer.Merge the organic layer generated, and then the saturated water-based sodium chloride solution washing of this resultant is used anhydrous magnesium sulfate drying.This siccative is filtered out, and then by this solvent vapourisation under reduced pressure.The resistates generated is filtered by NH silica gel (ethyl acetate) and is used for purifying to obtain a kind of thick title compound (72g).
1H-NMR(400MHz,CDCl 3)δ(ppm):1.13(d,J＝6.3Hz,3H),2.34(dd,J＝9.4,12.1Hz,1H),2.68(dd,J＝3.1,12.1Hz,1H),3.72(d,J＝2.0Hz,2H),3.75-3.79(m,1H),3.80(s,3H),3.82(s,3H),6.39-6.48(m,2H),7.10(d,J＝8.2Hz,1H)。
(2) (R)-N-(2,4-dimethoxy-benzyl)-N-(2-hydroxypropyl)-3,3-dimethoxy propionic acid amide synthesis
At room temperature, to the compound, 3-dimethoxy propionic acid (the CAS numbering 6191-98-6 that obtain in production instance 1-(1) (74.7g, 332mmol); 38.5g, 287mmol), DIPEA (173mL is added in the solution of EDC (95g, 497mmol) and HOBT (67.2g, 497mmol) in DMF (500mL), 995mmol), and this mixture is stirred 14 hours.Water (1L) and ethyl acetate (1L) are added in this reaction mixture to be separated this organic layer.The organic layers with water (1L) of this generation and saturated sodium chloride aqueous solution are washed, then uses anhydrous magnesium sulfate drying, this siccative is filtered out, and by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain this title compound (61g, 179mmol) by NH-silica gel column chromatography (normal heptane/ethyl acetate).
ESI-MS m/z 342[M+H] +
(3) (R)-4-(2,4-dimethoxy-benzyl)-2-methyl-3,4-dihydros-Isosorbide-5-Nitrae-oxygen azatropylidene-5 (2H)- the synthesis of ketone
At room temperature, to the compound (53.5g obtained in production instance 1-(2), add PPTS (19.7g, 78.4mmol) in solution 157mmol) in toluene (900mL), and then this mixture is heated 7 hours under reflux.This reaction mixture is cooled to room temperature, and then adds saturated water-based sodium hydrogen carbonate solution with ethyl acetate to be separated this organic layer.The saturated water-based sodium chloride solution of the organic layer of this generation is washed, and then uses anhydrous magnesium sulfate drying, this siccative is filtered out, and then by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain this title compound (30.5g, 110mmol) by NH-silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.19(d,J＝6.6Hz,3H),3.39-3.44(m,2H),3.80(s,3H),3.82(s,3H),4.03-4.11(m,1H),4.44(d,J＝14.5Hz,1H),4.73(d,J＝14.5Hz,1H),5.08(d,J＝8.2Hz,1H),6.43-6.48(m,3H),7.24(d,J＝9.0Hz,1H)。
(4) (R)-4-(2,4-dimethoxy-benzyl)-2-methyl isophthalic acid, 4-oxo azepine alkane-5-ketonesynthesis
At room temperature, to the compound (30.5g obtained in production instance 1-(3), palladium hydroxide/carbon (the 3g of 20% is added in solution 110mmol) in methyl alcohol (500mL), comprise 50% water-content), and this mixture is stirred 18 hours at 40 DEG C under a hydrogen atmosphere.This reaction mixture is cooled to room temperature, and is then filtered by Celite (trade mark), and filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain this title compound (29.1g, 104mmol) by silica gel column chromatography (ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.05(d,J＝6.6Hz,3H),2.60(dd,J＝5.1,15.6Hz,1H),2.92(ddd,J＝2.2,11.0,15.4Hz,1H),3.20(d,J＝15.2Hz,1H),3.29-3.38(m,1H),3.40-3.50(m,1H),3.56-3.66(m,1H),3.81(s,3H),3.82(s,3H),3.96(ddd,J＝2.3,5.5,12.5Hz,1H),4.37(d,J＝14.5Hz,1H),4.70(d,J＝14.5Hz,1H),6.43-6.48(m,2H),7.21(d,J＝8.6Hz,1H)。
(5) (R)-2-methyl isophthalic acid, 4-oxo azepine alkane-5-ketonesynthesis
At room temperature, to the compound (30.5g obtained in production instance 1-(4), add triethyl silicane (26.2mL, 164mmol) in solution 110mmol) in TFA (150mL), and this mixture is stirred 3 hours at 60 DEG C.This reaction mixture is cooled to room temperature and then under reduced pressure concentrates.Silica gel column chromatography (ethyl acetate/methanol) is used to carry out purifying, to obtain this title compound (12.3g, 95mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):1.19(d,J＝6.3Hz,3H),2.48-2.58(m,1H),2.89(ddd,J＝2.5,10.9,15.4Hz,1H),3.03(ddd,J＝0.9,7.6,15.3Hz,1H),3.35(ddd,J＝3.9,8.4,15.4Hz,1H),3.57-3.76(m,2H),4.01(ddd,J＝2.5,5.3,12.7Hz,1H),5.85-6.07(m,1H)。
(6) (R) synthesis of-5-methoxyl group-2-methyl-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
At room temperature, to the compound (13.4g obtained in production instance 1-(5), add trimethylammonium oxygen Tetrafluoroboric acid (6.8g, 114mmol) in solution 103mmol) in DCM (500mL), and this mixture is stirred 18 hours.In this reaction mixture, add saturated water-based sodium hydrogen carbonate solution, and this organic layer is separated.In the water layer of this generation, add DCM, and this organic layer is separated.The organic layer of this generation is merged, the saturated water-based sodium chloride solution of this resultant is washed, then by this resultant anhydrous magnesium sulfate drying, and then this siccative is filtered out, and by this solvent vapourisation under reduced pressure, to obtain title compound (13.7g, 96mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.19(d,J＝6.4Hz,3H),2.42(ddd,J＝1.2,4.5,15.6Hz,1H),2.81-2.92(m,1H),3.33-3.42(m,1H),3.47-3.59(m,3H),3.61(s,3H),3.85-3.93(m,1H)。
Production instance 2
(R)-2-methyl isophthalic acid, the synthesis of 4-oxo azepine alkane-5-ketone
(1) (R)-tert-butyl (2-(2-cyanoethoxy) propyl group) carbamatesynthesis
At room temperature, to (R)-tert-butyl (2-hydroxypropyl) carbamate (CAS numbering 119768-44-4; 71.0g, 405mmol) add DBU (27.3mL, 182mmol) in solution in vinyl cyanide (400mL), and this mixture is stirred 5 hours at that same temperature.Acetic acid (10.4mL, 182mmol) is added in reaction mixture, and mixture is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain this title compound (63.1g, 276mmol) by NH-silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.10-1.20(m,3H),1.45(s,9H),2.59(dd,J＝6.3,6.3Hz,2H),2.96-3.11(m,1H),3.23-3.41(m,1H),3.52-3.66(m,1H),3.61(td,J＝6.3,9.2Hz,1H),3.75(td,J＝6.3,9.2Hz,1H),4.88(brs,1H)。
(2) (R)-methyl 3-((1-aminopropan-2-base) oxygen base) propionate hydrochloridesynthesis
At room temperature, compound (the 63.1g that will obtain in production instance 2-(1), 276mmol) be dissolved in hydrogenchloride/1 of 4M, in 4-dioxane solution (691mL) and 5% to 10% hydrogenchloride/methanol solution (140mL), and this mixture is stirred 3 hours at 50 DEG C.Hydrogenchloride/Isosorbide-5-Nitrae-diox (311mL) of 4M is added in this reaction mixture further, and this mixture is stirred 3 hours at 50 DEG C, and then this resultant is under reduced pressure concentrated.Diethyl ether is added to this resistates and this resultant is under reduced pressure concentrated, to obtain thick title compound (76.9g).
ESI-MS m/z 162[M+H]+
(3) (R)-2-methyl isophthalic acid, 4-oxo azepine alkane-5-ketonesynthesis
At room temperature, DBU (132mL is added in the solution of the compound (76.9g) obtained in the production instance 2-(2) in methyl alcohol (693mL), 884mmol), and this mixture is heated 16 hours under reflux.This reaction mixture is cooled to room temperature and then under reduced pressure concentrates.The resistates of this generation is used silica gel column chromatography (ethyl acetate/methanol) purifying twice, to obtain title compound (21.5g, 166mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.19(d,J＝6.3Hz,3H),2.48-2.58(m,1H),2.89(ddd,J＝2.5,10.9,15.4Hz,1H),3.03(ddd,J＝0.9,7.6,15.3Hz,1H),3.35(ddd,J＝3.9,8.4,15.4Hz,1H),3.57-3.76(m,2H),4.01(ddd,J＝2.5,5.3,12.7Hz,1H),5.85-6.07(m,1H)。
ESI-MS m/z 130[M+H]+
Production instance 3
(S) synthesis of-2-(methyl fluoride)-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
(1) (S)-1-(benzyloxy)-3-((2,4-dimethoxy-benzyl) is amino) propan-2-olsynthesis
To 2,4-dimethoxybenzylamine (CAS numbering 20781-20-8 under water cooling; 46.7mL, 310.6mmol) and (S)-(+)-benzyl glycidyl ether (CAS numbering 16495-13-9; 50.0g, 304.5mmol) add two (trifluoromethane sulfonyl group) imine lithium (87g, 304.5mmol) in solution in DCM (1.0L).At room temperature this reaction mixture is stirred 20 hours.Water is added, to be separated this organic layer in this reaction mixture.This organic over anhydrous dried over mgso.By this solvent vapourisation under reduced pressure, to obtain thick title compound (119.4g).
ESI-MS m/z 332[M+H]+
(2) (S)-N-(3-(benzyloxy)-2-hydroxypropyl)-N-(2,4-dimethoxy-benzyl)-3,3-dimethoxys the synthesis of propionic acid amide
At room temperature, to the compound (119.4g), 3 obtained in production instance 3-(1), 3-dimethoxy propionic acid (47.0g, 350.1mmol) and in the solution of DIPEA (159mL) in DMF (800mL) add EDC (88g, 456.7mmol) and HOBT (456.7mmol).This reaction mixture is stirred 16 hours, and then adds ethyl acetate and saturated water-based sodium chloride solution.This organic layer is separated and washs with saturated water-based sodium chloride solution.Organic over anhydrous dried over mgso.This organic layer is filtered by silicagel pad (NH silica gel+silica gel, ethyl acetate).The filtrate of generation is under reduced pressure concentrated, to obtain thick title compound (125.5g).
ESI-MS m/z 470[M+Na]+
(3) (S)-2-((benzyloxy) methyl)-4-(2,4-dimethoxy-benzyl)-3,4-dihydros-Isosorbide-5-Nitrae-oxygen azepine tall and erect-5 (2H)-onesynthesis
The compound obtained in production instance 3-(2) (125.5g) and the solution of PPTS (35.2g, 140.2mmol) in dimethylbenzene (1L) are heated 6 hours under reflux.This reaction mixture is cooled to room temperature, and in this reaction mixture, adds ethyl acetate with saturated water-based sodium hydrogen carbonate solution to be separated this organic layer.This organic layer is carried out washing with saturated water-based sodium chloride solution and then carries out drying with anhydrous magnesium sulfate.This organic layer is under reduced pressure concentrated and resistates column chromatography (normal heptane/ethyl acetate) purifying that will generate, to obtain title product (57.7g, 150mmol).
ESI-MS m/z 384[M+H]+,406[M+Na]+
(4) (S)-4-(2,4-dimethoxy-benzyl)-2-(methylol)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketonesynthesis
Under a hydrogen atmosphere at 4MPa to 5MPa and 70 DEG C, compound (the 57.7g that will obtain in production instance 3-(3), 150.5mmol), the palladium hydroxide/carbon (6g comprises the water-content of 50%) of 20%, the mixture of acetic acid (20mL) and ethanol (600mL) stir 50 hours.This reaction mixture is cooled to room temperature.Insolubles is filtered out by Celite (trade mark) and uses ethyl acetate to wash on this resultant.This filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (33.7g) by silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.83(dd,J＝5.1,7.0Hz,1H),2.63(dd,J＝5.1,15.2Hz,1H),2.95(ddd,J＝2.7,11.3,15.6Hz,1H),3.22-3.30(m,2H),3.40-3.45(m,2H),3.51(dd,J＝8.2,16.0Hz,1H),3.62-3.67(m,1H),3.80(s,3H),3.81(s,3H),4.04(ddd,J＝2.3,5.1,12.5Hz,1H),4.36(d,J＝14.5Hz,1H),4.73(d,J＝14.5Hz,1H),6.43-6.47(m,2H),7.22(d,J＝8.6Hz,1H)。
ESI-MS m/z 296[M+H]+,318[M+Na]+
(5) (S)-4-(2,4-dimethoxy-benzyl)-2-(methyl fluoride)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketonesynthesis
At room temperature; compound (the 33.7g obtained in production instance 3-(4); 114.1mmol), DIPEA (49.2mL; 285.3mmol) and TBuA difluorotriphenylsilicate (73.9g; solution 136.9mmol) in THF (600mL) adds perfluorinated butane perfluorobutanesulfonyl fluoride (45.1mL, 251.0mmol).At room temperature this reaction mixture is stirred 64 hours.This reaction mixture is under reduced pressure concentrated.The mixed solvent of toluene/ethyl acetate (5/1) and saturated water-based sodium chloride solution is added, to be separated this organic layer in the resistates of this generation.Saturated water-based sodium chloride solution is used by this organic layer to wash twice further.This organic layer is under reduced pressure concentrated and the resistates of generation is used continuously silica gel column chromatography (normal heptane/ethyl acetate) and NH silica gel column chromatography (normal heptane/ethyl acetate) purifying, to obtain thick title compound (41g).
1H-NMR(400MHz,CDCl3)δ(ppm):2.62(dd,J＝5.5,15.2Hz,1H),2.96(ddd,J＝2.3,11.3,15.2Hz,1H),3.35-3.68(m,4H),3.80(s,3H),3.81(s,3H),4.00(ddd,J＝2.3,5.1,12.5Hz,1H),4.09-4.36(m,2H),4.40(d,J＝14.5Hz,1H),4.74(d,J＝14.5Hz,1H),6.44-6.47(m,2H),7.24(d,J＝8.2Hz,1H)。
ESI-MS m/z 298[M+H]+
(6) (S)-2-(methyl fluoride)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketonesynthesis
At room temperature, in the solution of the compound (41g) obtained in the production instance 3-(5) in TFA (300mL), triethyl silicane (27.4mL, 171.7mmol) is added.This reaction mixture is stirred 3 hours at 60 DEG C.This reaction mixture is under reduced pressure concentrated.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) is used to carry out purifying, to obtain title compound (15g, 101.94mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):2.54(ddd,J＝2.0,5.1,15.6Hz,1H),2.93(ddd,J＝2.7,11.3,15.6Hz,1H),3.23-3.31(m,1H),3.46(ddd,J＝3.5,8.6,15.2Hz,1H),3.66-3.78(m,2H),4.07(ddd,J＝2.7,5.1,12.5Hz,1H),4.24-4.53(m,2H),6.50(brs,1H)。
(7) (S)-2-(methyl fluoride)-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidenesynthesis
At room temperature, in the solution of the compound (15g, 101.94mmol) obtained in the production instance 3-(6) in DCM (400mL), trimethylammonium oxygen a tetrafluoro borate is added.This reaction soln is at room temperature stirred 14 hours.Saturated aqueous sodium bicarbonate solution is added in this reaction mixture, and this mixture is at room temperature stirred 30 minutes.Chloroform is added, to be separated this organic layer in this mixture.Organic over anhydrous dried over mgso.This organic layer is under reduced pressure concentrated, to obtain title compound (14.9g, 93mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.47(ddd,J＝1.2,4.3,15.6Hz,1H),2.87-2.96(m,1H),3.45-3.70(m,4H),3.63(s,3H),3.98(ddd,J＝3.1,4.3,12.1Hz,1H),4.30-4.50(m,2H)。
Production instance 4
(S) synthesis of-2-(methyl fluoride)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone
(1) (S) the fluoro-2-hydroxypropyl of-3--4-tosylate synthesis
To (R, R)-(-)-N, N'-two (3,5-bis--tert-butyl salicylidene)-1,2-hexanaphthene diamino cobalt (II) (9.26g, 15.3mmol), HFIP (64.4mL, 613mmol) and in the mixture of DBN (1.51mL, 12.3mmol), add diethyl ether (1.00L), (2R)-(-)-glycidyl tosylat (CAS numbering 113826-06-5; 50.0g, 219mmol) and benzoyl fluoride (33.4mL, 307mmol).At room temperature, the stirring of this reaction mixture spent the night and then add the ammonia/methanol solution (150mL) of 7M.At room temperature this mixture is stirred 2 hours, and by this solvent vapourisation under reduced pressure.Ethyl acetate (300mL) is added in the resistates generated, and by this resultant water and saturated water-based sodium chloride solution continuous washing.By this organic over anhydrous dried over mgso, and under reduced pressure this solvent is evaporated.The resistates of this generation is carried out purifying, to obtain title compound (45.5g, 183mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.28-2.42(m,1H),2.46(s,3H),4.03-4.18(m,3H),4.34-4.54(m,2H),7.37(d,J＝8.2Hz,2H),7.81(d,J＝8.2Hz,2H)。
ESI-MS m/z 271[M+Na]+
(2) (S, E)-methyl 3-((the fluoro-3-of 1-(tosyl group oxygen base) the third-2-base) oxygen base) acrylate 's synthesis
Compound (45.5g, 183mmol), the NMM (12.1mL, 110mmol) and methyl propionate (CAS numbering 922-67-8 that will obtain in production instance 4-(1); 19.8mL, 238mmol) solution in THF (315mL) stirs 3 hours under ice-cooling.Acetic acid (6.29mL, 110mmol) is added in reaction mixture, and then adds water and ethyl acetate.By this organic layer be separated and continuous water and saturated water-based sodium chloride solution wash.Organic over anhydrous magnesium sulfate is carried out drying and then under reduced pressure concentrates.The resistates of this generation is carried out purifying, to obtain title compound (49.2g, 148mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.46(s,3H),3.70(s,3H),4.11-4.37(m,3H),4.42-4.66(m,2H),5.26(d,J＝12.5Hz,1H),7.33-7.42(m,3H),7.76-7.83(m,2H)。
ESI-MS m/z 355[M+Na]+
(3) (S) conjunction of-methyl 3-((the fluoro-3-of 1-(tosyl group oxygen base) the third-2-base) oxygen base) propionic ester become
Under a hydrogen atmosphere at room temperature, by the compound (48.8g obtained in production instance 4-(2) in ethanol (279mL), the suspension agitation of the palladium/carbon (6.25g comprises the water-content of 50%) of 147mmol) He 5% 2 hours.Insolubles is removed, and then this filtrate is under reduced pressure concentrated, to obtain thick title compound (45.8g).
1H-NMR(400MHz,CDCl3)δ(ppm):2.46(s,3H),2.53(t,J＝6.3Hz,2H),3.68(s,3H),3.27-3.87(m,3H),4.08(dt,J＝1.6,5.5Hz,2H),4.29-4.53(m,2H),7.36(d,J＝8.2Hz,2H),7.80(d,J＝8.2Hz,2H)。
ESI-MS m/z 357[M+Na]+
(4) (S) synthesis of-2-(methyl fluoride)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone
The compound that will obtain in production instance 4-(3) (45.8g, 137mmol) and the mixture of 7M ammonia/methanol solution (391mL, 2.74mol) stir 2 hours at 130 DEG C in high-pressure sterilizing pot.This reaction mixture is cooled to room temperature, and then this mixture is under reduced pressure concentrated.At room temperature, in this resistates, methyl alcohol (300mL) and DBU (41.0mL, 274mmol) is added.This reaction mixture is stirred 3 hours at 100 DEG C.This reaction mixture is cooled to room temperature and then vapourisation under reduced pressure.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate methanol) is used to carry out purifying, to obtain title compound (10.4g, 70.7mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):2.54(ddd,J＝2.0,5.1,15.6Hz,1H)2.93(ddd,J＝2.7,11.3,15.6Hz,1H),3.23-3.31(m,1H),3.46(ddd,J＝3.5,8.6,15.2Hz,1H)3.66-3.78(m,2H),4.07(ddd,J＝2.7,5.1,12.5Hz,1H),4.24-4.53(m,2H),6.50(brs,1H)。
ESI-MS m/z 295[M+M+H]+
Production instance 5
(S) synthesis of-2-(difluoromethyl)-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
(1) (S) conjunction of-2-(difluoromethyl)-4-(2,4-dimethoxy-benzyl)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone become
Under nitrogen atmosphere at-78 DEG C, in the solution of DMSO (1.03mL, 14.5mmol) in THF (60mL), add oxalyl chloride (1.18mL, 14.0mmol).This mixture is stirred 10 minutes at-78 DEG C and dropwise added at the same temperature by the solution of compound in THF (40mL) obtained in production instance 3-(4) (3.30g, 11.2mmol).After at that same temperature this mixture being stirred 1 hour, dropwise add DIPEA (7.79mL, 44.7mmol).After 10 minutes, this reaction mixture is heated to room temperature and stirs 1 hour further.Aqueous ammonium chloride solution and ethyl acetate are added in this mixture to be separated this organic layer.Saturated water-based sodium chloride solution is used by this organic layer to carry out washing and using anhydrous magnesium sulfate drying.This organic layer is under reduced pressure concentrated.The resistates of generation to be dissolved in DCM (66mL) and this resultant is cooled to-78 DEG C.At that same temperature, BAST (6.18mL, 33.5mmol) is added in this mixture, then this resultant is slowly heated to room temperature and stir 15 hours.Saturated water-based sodium chloride solution and ethyl acetate is added, to be separated this organic layer in this reaction mixture.Saturated water-based sodium chloride solution is used by this organic layer to carry out washing and using anhydrous magnesium sulfate drying.This organic layer is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (1.13g, 3.58mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.63(dd,J＝5.1,15.6Hz,1H),2.97(ddd,J＝2.4,11.4,15.6Hz,1H),3.26-3.36(m,1H),3.60(d,J＝4.7Hz,2H),3.77-3.84(m,1H),3.80(s,3H),3.81(s,3H),4.04-4.10(m,1H),4.36(d,J＝14.1Hz,1H),4.75(d,J＝14.1Hz,1H),5.47-5.76(m,1H),6.44-6.47(m,2H),7.24-7.27(m,1H)。
ESI-MS m/z 316[M+H]+
(2) (S) synthesis of-2-(difluoromethyl)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone
At room temperature, in the solution of the compound (1.16g, 3.68mmol) obtained in the production instance 5-(1) in TFA (10mL), triethyl silicane (0.881mL, 5.52mmol) is added.This reaction mixture is stirred 3 hours at 60 DEG C.This reaction mixture is cooled to room temperature and by this solvent vapourisation under reduced pressure.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) is used to carry out purifying, to obtain title compound (472mg, 2.86mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):2.57(ddd,J＝1.9,4.8,15.7Hz,1H),2.95(ddd,J＝2.7,11.3,15.6Hz,1H),3.35(dd,J＝7.8,15.4Hz,1H),3.54(ddd,J＝3.7,8.8,15.5Hz,1H),3.63-3.78(m,2H),4.14(ddd,J＝2.7,5.0,12.8Hz,1H),5.63-5.92(m,1H),6.00(brs,1H)。
(3) (S) synthesis of-2-(difluoromethyl)-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
Under ice-cooling, in the solution of the compound (580mg, 3.51mmol) obtained in the production instance 5-(2) in DCM (100mL), trimethylammonium oxygen a tetrafluoro borate (597mg, 4.04mmol) is added.This reaction mixture is stirred 20 minutes under ice-cooling, then heats to room temperature, and stir 14 hours further.Saturated aqueous sodium bicarbonate solution is added in this reaction mixture, and this mixture is at room temperature stirred 30 minutes.Chloroform is added, to be separated this organic layer in this mixture.Organic over anhydrous dried over mgso.This organic layer is under reduced pressure concentrated, to obtain title compound (450mg, 2.51mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.47(ddd,J＝1.2,4.2,15.6Hz,1H),2.89-2.97(m,1H),3.46-3.61(m,3H),3.64(s,3H),3.77(d,J＝14.5Hz,1H),3.98-4.05(m,1H),5.57-5.86(m,1H)。
Production instance 6
(R) synthesis of-2-ethyl-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
(1) (R) synthesis of-1-((2,4-dimethoxy-benzyl) is amino) fourth-2-alcohol
According to the method for production instance 3-(1), thick title compound (15.7g) is obtained from (R)-(+)-1,2-butylene oxide ring (CAS numbering 3760-95-0; 5.0g, 69mmol) and 2,4-dimethoxybenzylamine (15.7g, 65.8mmol).
ESI-MS m/z 240[M+H]+
(2) (R)-N-(2,4-dimethoxy-benzyl)-N-(2-hydroxyl butyl)-3,3-dimethoxy propionic acid amides synthesis
According to the method for production instance 1-(2), title compound (16.3g, 45.9mmol) be obtained from the compound (15.7g) obtained in production instance 6-(1) and 3,3-dimethoxy propionic acid (8.80g, 65.6mmol).
ESI-MS m/z 378[M+Na]+
(3) (R)-4-(2,4-dimethoxy-benzyl)-2-ethyl-3,4-dihydros-Isosorbide-5-Nitrae-oxygen azatropylidene-5 (2H)- the synthesis of ketone
According to the method for production instance 1-(3), title compound (5.88g, 20.2mmol) is obtained from the compound (16.3g, 45.9mmol) obtained in production instance 6-(2).
ESI-MS m/z 292[M+H]+
(4) (R) synthesis of-4-(2,4-dimethoxy-benzyl)-2-ethyl-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone
According to the method for production instance 1-(4), title compound (5.92g, 20.2mmol) is obtained from the compound (5.88g, 20.2mmol) obtained in production instance 6-(3).
ESI-MS m/z 316[M+Na]+
(5) (R) synthesis of-2-ethyl-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone
According to the method for production instance 1-(5), title compound (2.78g, 19.4mmol) is obtained from the compound (5.92g, 20.2mmol) obtained in production instance 6-(4).
1H-NMR(400MHz,CDCl3)δ(ppm):0.96(t,J＝7.6Hz,3H),1.38-1.50(m,1H),1.52-1.62(m,1H),2.54(dd,J＝4.5,15.4Hz,1H),2.82-2.94(m,1H),3.08(dd,J＝7.4,14.1Hz,1H),3.27-3.41(m,2H),3.63-3.74(m,1H),4.04(ddd,J＝2.3,5.3,12.7Hz,1H),6.02-6.22(m,1H)。
(6) (R) synthesis of-2-ethyl-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
According to the method for production instance 1-(6), title compound (2.51g, 16.0mmol) is obtained from the compound (2.78g, 19.4mmol) obtained in production instance 6-(5).
1H-NMR(400MHz,CDCl3)δ(ppm):0.95(t,J＝8.0Hz,3H),1.44-1.57(m,2H),2.43(ddd,J＝1.2,4.5,15.4Hz,1H),2.87(ddd,J＝3.1,11.5,15.0Hz,1H),3.24-3.32(m,1H),3.33-3.41(m,1H),3.47-3.57(m,2H),3.62(s,3H),3.87-3.95(m,1H)。
Production instance 7
(S) synthesis of-2-((benzyloxy) methyl)-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
(1) (R)-3-(benzyloxy)-2-hydroxypropyl 4-tosylate synthesis
Under ice-cooling, to (2R)-(-)-glycidyl tosylat (25.0g, 109mmol), phenylcarbinol (22.7mL, 219mmol) and in the mixture of toluene (200mL) add boron trifluoride-ether complex (0.694mL, 5.48mmol).This reaction mixture is at room temperature stirred and spends the night.This reaction mixture is washed twice with saturated water-based sodium hydrogen carbonate solution (50.0mL) and uses water (50.0mL) to wash twice further.Ethanol is added until this suspension becomes clarification to this organic layer.This resistates is carried out purifying, to obtain title compound (28.0g, 83.0mmol) by silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):2.40(d,J＝5.5Hz,1H),2.44(s,3H),3.46-3.57(m,2H),3.96-4.15(m,3H),4.50(s,2H),7.26-7.39(m,7H),7.75-7.82(m,2H)。
(2) (R, E)-methyl 3-((1-(benzyloxy)-3-(tosyl group oxygen base) the third-2-base) oxygen base) propylene the synthesis of acid esters
Compound (the 28.0g that will obtain in production instance 7-(1), 83.2mmol), Methyl propiolate (15.3mL, 183mmol), the mixture of NMM (9.15mL, 83.2mmol) and THF (280mL) at room temperature stirs and spends the night.This resistates is carried out purifying, to obtain title compound (34.7g, 82.5mmol) by silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):2.44(s,3H),3.57(dd,J＝1.8,4.9Hz,2H),3.69(s,3H),4.14-4.30(m,3H),4.44-4.55(m,2H),5.20(d,J＝12.5Hz,1H),7.24-7.40(m,8H),7.75-7.78(m,2H)。
(3) (R)-methyl 3-((1-(benzyloxy)-3-(tosyl group oxygen base) the third-2-base) oxygen base) propionic ester synthesis
10% palladium/carbon (4.39g comprises 50% water-content) is added in the solution of the compound (34.7g, 82.5mmol) obtained in the production instance 7-(2) in ethanol (347mL).This reaction mixture is stirred 7 hours under a hydrogen atmosphere.Insolubles is filtered out by Celite (trade mark).By this solvent vapourisation under reduced pressure, to obtain title compound (34.5g, 82.0mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.44(s,3H),2.51(t,J＝6.3Hz,2H),3.43-3.52(m,2H),3.66(s,3H),3.68-3.72(m,1H),3.74-3.85(m,2H),4.02-4.08(m,1H),4.11-4.18(m,1H),4.46(s,2H),7.21-7.26(m,2H),7.28-7.40(m,5H),7.74-7.82(m,2H)。
(4) (S) synthesis of-2-((benzyloxy) methyl)-Isosorbide-5-Nitrae-oxo azepine alkane-5-ketone
The compound (22.0g, 52.1mmol) that will obtain in production instance 7-(3) is dissolved in 7M ammonia/methanol solution (100mL, 700mmol).This reaction mixture is spent the night 100 DEG C of stirrings in sealed tube.This reaction mixture to be transferred in eggplant shape flask and to add DBU (24.9mL, 167mmol).This reaction mixture is stirred 6 hours at 80 DEG C.This resultant is cooled to room temperature and by this solvent vapourisation under reduced pressure.This resistates is carried out purifying, to obtain title compound (5.56g, 23.6mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.48-2.56(m,1H),2.91(ddd,J＝2.7,11.0,15.5Hz,1H),3.24-3.33(m,1H),3.35-3.44(m,2H),3.53(dd,J＝4.7,9.8Hz,1H),3.61-3.76(m,2H),4.04(ddd,J＝2.7,5.2,12.8Hz,1H),4.49-4.60(m,2H),5.92(brs,1H),7.27-7.41(m,5H)。
(5) (S) synthesis of-2-((benzyloxy) methyl)-5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene
At room temperature, to the compound (2.00g obtained in production instance 7-(4), trimethylammonium oxygen a tetrafluoro borate (1.51g is added in solution 8.50mmol) in DCM (40.0mL), 10.2mmol), and this mixture is stirred 15 hours.Saturated aqueous sodium bicarbonate solution is added in this reaction mixture, and this mixture is at room temperature stirred 20 minutes.This organic layer is separated and uses anhydrous magnesium sulfate drying.By this solvent vapourisation under reduced pressure, to obtain title compound (2.12g, 8.50mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.44(ddd,1.2,4.4,15.5Hz,1H),2.90(ddd,J＝3.1,11.6,15.3Hz,1H),3.41-3.65(m,9H),3.97(ddd,J＝3.1,4.6,12.2Hz,1H),4.53-4.60(m,2H),7.27-7.42(m,5H)。
Production instance 8
(R)-methyl 3-chloro-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters synthesis
(1) (R)-methyl 3-amino-2-(2-methyl isophthalic acid, 4-oxo azepine alkane-5-subunit)-3-oxopropanoic acid Lipase absobed
The compound (16.0g, 156mmol) that will obtain in production instance 1-(6) and carbamyl methyl acetate (CAS numbering 51513-29-2; 18.3g, 156mmol) solution in THF (40mL)/DMF (10mL) stirs 15 hours at 90 DEG C.This reaction mixture is cooled to room temperature and by this solvent vapourisation under reduced pressure.Silica gel chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) is used to carry out purifying, to obtain title compound (14.2g, 62.2mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):1.20(d,J＝6.3Hz,3H),2.73-2.81(m,1H),3.33-3.66(m,5H),3.77(s,3H),4.04-4.10(m,1H)。
(2) (R)-methyl 6-methyl-3-oxo-2,3,5,6,8,9-six hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine the synthesis of Zhuo-1-carboxylicesters
At room temperature, to the compound (14.2g obtained in product example 8-(1), iodobenzene diacetate (24.1g is added in solution 62.2mmol) in THF (100mL)/toluene (100mL), 74.7mmol), and this mixture is at room temperature stirred 60 hours.Saturated aqueous sodium bicarbonate solution (60mL) and saturated water-based sodium sulfite solution (60mL) are added in this reaction mixture, and this mixture is at room temperature stirred 1 hour.This mixture is made to be extracted with ethyl acetate three times.The organic over anhydrous dried over mgso merged also under reduced pressure concentrates.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) is used to carry out purifying, to obtain title compound (9.97g, 44.1mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.3Hz,3H),2.86(ddd,J＝2.4,11.0,16.3Hz,1H),3.45(dd,J＝9.0,14.7Hz,1H),3.53-3.70(m,3H),3.83(s,3H),4.13-4.19(m,1H),4.29(d,J＝14.7Hz,1H),8.03(brs,1H)。
ESI-MS m/z 227[M+H]+
(3) (R)-methyl 3-chloro-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-also the synthesis of carboxylicesters
The compound (9.97g, 44.1mmol) that will obtain in production instance 8-(2) and the mixture of phosphoryl chloride (60mL) stir 4 hours at 110 DEG C.This reaction mixture is cooled to room temperature and under reduced pressure concentrates.The resistates of this generation is carried out purifying, to obtain title compound (5.94g, 24.3mmol) by NH-silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.30(d,J＝6.5Hz,3H),3.02(ddd,J＝2.7,10.8,16.4Hz,1H),3.55-3.62(m,1H),3.66-3.74(m,1H),3.87(s,3H),3.88-3.98(m,2H),4.13-4.19(m,1H),4.26-4.31(m,1H)。
ESI-MS m/z 245[M+H]+
Production instance 9
(S)-chloro-the 6-of methyl 3-(methyl fluoride)-5,6,8,9-imidazolidine is [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylic acid also the synthesis of ester
According to production instance 8-(1), 8-(2), with 8-(3), title compound (1.77g, 6.74mmol) is obtained from the compound (9.39g, 58.3mmol) obtained in production instance 3-(7).
1H-NMR(400MHz,CDCl3)δ(ppm):3.02(ddd,J＝2.7,11.4,16.4Hz,1H),3.58-3.65(m,1H),3.71-3.80(m,1H),3.88(s,3H),3.98-4.09(m,2H),4.23-4.28(m,1H),4.33-4.65(m,3H)。
ESI-MS m/z 263[M+H]+
Production instance 10
the synthesis of chloro-5,6,8, the 9-imidazolidines of methyl 3-also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
(1) methyl 3-oxo-2,3,5,6,8,9-six hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylic acid the synthesis of ester
According to the method for production instance 8-(1) and 8-(2), title compound (13.0g, 6.74mmol) is obtained from 5-methoxyl group-2,3,6,7-tetrahydrochysenes-Isosorbide-5-Nitrae-oxygen azatropylidene (CAS numbering 384330-36-3; 25.0g, 194mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):3.26-3.30(m,2H),3.76-3.85(m,4H),3.83(s,3H),4.00-4.03(m,2H),8.20(brs,1H)。
ESI-MS m/z 213[M+H]+
(2) the conjunction of methyl 3-chloro-5,6,8,9-six hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters become
According to the method for production instance 8-(3), title compound (7.58g, 32.9mmol) is obtained from the compound (11g, 51.8mmol) obtained in production instance 10-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):3.51-3.55(m,2H),3.85-3.89(m,4H),3.89(s,3H),4.25-4.28(m,2H)。
Production instance 11
the synthesis of bromo-5,6,8, the 9-imidazolidines of methyl 3-also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
To the compound (7.64g obtained in production instance 10-(1), phosphorus oxybromide (25.0g is added in solution 36.0mmol) in toluene (140mL), 87.2mmol), and by this mixture undertaken stirring and heat 24 hours under reflux.This reaction mixture is cooled to room temperature, adds ice and saturated water-based sodium hydrogen carbonate solution, and this mixture is stirred 3 hours.This solid filtering is gone out and this filtrate is used chloroform extraction three times.The organic over anhydrous sodium sulfate of generation is carried out drying and then this resultant is under reduced pressure concentrated.Ethyl acetate is used to wash three times, to obtain this title compound (3.18g, 11.6mmol) resistates of this generation.This filtrate is concentrated and the resistates of this generation is carried out purifying, to obtain title compound (0.84g, 3.1mmol) by NH-silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):3.42-3.61(m,2H),3.80-3.89(m,4H),3.86(s,3H),4.25(t,J＝3.5Hz,2H)。
Production instance 12
(3-chloro-4-ring propoxyphenyl) boric acid
At-78 DEG C, n-Butyl Lithium/n-heptane solution (2.69mol/L, 1.70mL) is dropwise added into the bromo-2-of 4-chloro-1-ring propoxy-benzene (CAS 869569-68-6; 1.10g, 4.44mmol) in solution in THF (8.5mL), and this mixture is stirred 30 minutes at that same temperature.Boric acid triethyl ester (0.980mL, 5.79mmol) is slowly added in this reaction mixture, then dry ice is removed from cooling bath, and then this mixture is stirred until internal temperature is increased to 0 DEG C.Saturated aqueous ammonium chloride solution and ethyl acetate are added in this mixture, to be separated this organic layer.Used by resultant saturated water-based sodium chloride solution to carry out washing and using anhydrous magnesium sulfate drying, and under reduced pressure concentrate.Ether is added in the resistates of generation, and the solid by filtration of generation is collected, to obtain title compound (520mg, 2.45mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.85-0.98(m,4H),3.87-3.98(m,1H),7.43(d,J＝8.2Hz,1H),8.09(dd,J＝1.6,8.2Hz,1H),8.14(d,J＝1.6Hz,1H)。
Production instance 13
the conjunction of 2-(the chloro-4-of 3-(methoxymethoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes become
By bromo-for 4-2-chloro-1-(methoxymethoxy) benzene (CAS 1301146-84-8; 4.85g, 19.3mmol), two (pinacol ester) two boron (6.87g, 27.1mmol), potassium acetate (5.73g, 58.4mmol) and the mixture of Pd (dppf) Cl2CH2Cl2 (0.788g, 0.964mmol) in DMSO (76mL) 80 DEG C stir 5 hours.Water and diethyl ether is added, to be separated this organic layer in this reaction mixture.Used by this organic layer saturated water-based sodium chloride solution to carry out washing and using anhydrous magnesium sulfate drying, and under reduced pressure concentrate.The resistates of this generation is carried out purifying, to obtain title compound (4.50g, 15.1mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.33(s,12H),3.51(s,3H),5.28(s,2H),7.15(d,J＝8.2Hz,1H),7.64(dd,J＝1.6,8.2Hz,1H),7.82(d,J＝1.6Hz,1H)。
Production instance 14
2-(4-ring propoxy--3-(trifluoromethoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes synthesis
According to the method for production instance 13, title compound (1.05g, 3.05mmol) is obtained from 4-bromo-1-ring propoxy--2-(trifluoromethoxy) benzene (CAS 1337606-89-9; 1.30g, 4.38mmol).
1H-NMR(400MHz，CDCl3)δ(ppm):0.76-0.84(m,4H),1.33(s,12H),3.76-3.90(m,1H),7.31(d,J＝8.2Hz,1H),7.63(qd,J＝1.3,1.5Hz,1H),7.70(dd,J＝1.5,8.2Hz,1H)。
Production instance 15
2-(the synthesis of the chloro-4-of 3-(ring propoxyphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes
According to the method for production instance 13, title compound (1.10g, 3.73mmol) is obtained from the bromo-2-of 4-chloro-1-ring propoxy-benzene (CAS 869569-68-6; 1.10g, 4.44mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.74-0.96(m,4H),1.33(s,12H),3.71-3.94(m,1H),7.28(d,J＝8.2Hz,1H),7.67(dd,J＝1.6,8.2Hz,1H),7.78(d,J＝1.6Hz,1H)。
Production instance 16
the synthesis of 2-(4-ring propoxy--3-aminomethyl phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes
According to the method for production instance 13, title compound (1.20g, 4.38mmol) is obtained from 4-bromo-1-ring propoxy--2-toluene (CAS 1243345-41-6; 2.00g, 8.81mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.62-0.85(m,4H),1.33(s,12H),2.16(s,3H),3.71-3.81(m,1H),7.19(d,J＝8.2Hz,1H),7.58(brs,1H),7.65(brd,J＝8.2Hz,1H)。
Production instance 17
2-(4-(difluoro-methoxy)-3-((methoxymethoxy) methyl) phenyl)-4,4,5,5-tetramethyl-s-1,3,2-bis- the synthesis of oxa-ring pentaborane
(1) the synthesis of the bromo-1-of 4-(difluoro-methoxy)-2-((methoxymethoxy) methyl) benzene
Under ice-cooling, to the bromo-2-of 5-(difluoro-methoxy) phenyl aldehyde (CAS numbering 329269-64-9; 750mg, 2.99mmol) add sodium borohydride (113mg, 2.99mmol) in solution in methyl alcohol (15mL).This reaction mixture is stirred 30 minutes under ice-cooling.Acetic acid is added in reaction mixture, and this mixture is heated to room temperature, and then under reduced pressure this solvent is evaporated.This resistates and methanol mixed are carried out constant boiling point to evaporate three times and mix with chloroform further and carry out constant boiling point evaporation.The resistates of generation is dissolved in DCM.Methylal(dimethoxymethane) (5.29mL, 59.8mmol) is added in the solution of generation.Under ice-cooling to Vanadium Pentoxide in FLAKES (4.24g, 29.9mmol) in this reaction mixture.This reaction mixture is stirred 30 minutes under ice-cooling.Salt of wormwood (20g, 145mmol) is added in this reaction soln, and then this mixture is heated to room temperature.This reaction soln is carried out filtering and then filtrate under reduced pressure being concentrated.The resistates of this generation is carried out purifying, to obtain title compound (622mg, 2.09mmol) by silica gel chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):3.42(s,3H),4.62(s,2H),4.74(s,2H),6.50(t,J＝73.8Hz,1H)7.03(d,J＝8.6Hz,1H)7.43(dd,J＝2.3,8.6Hz,1H)7.65(d,J＝2.3Hz,1H)。
(2) 2-(4-(difluoro-methoxy)-3-((methoxymethoxy)methyl) phenyl) synthesis of-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes
At room temperature, to the compound (622mg obtained in production instance 17-(1) in DMF (10mL), 2.09mmol), potassium acetate (616mg, 6.28mmol) and two (pinacol ester) two boron (1.06g, Pd (dppf) Cl2CH2Cl2 (171mg, 209 μm of ol) is added in solution 4.19mmol).This reaction mixture is stirred 2 hours at 110 DEG C and is then cooled to room temperature.This reaction soln ethyl acetate is diluted, then washes this resultant with water five times and then use saturated water-based sodium chloride solution to wash.By this organic over anhydrous dried over sodium sulfate, and by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain thick title compound (726mg) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.34(s,12H),3.42(s,3H),4.64(s,2H),4.73,(s,2H),6.55(dt,J＝1.2,74.2Hz,1H),7.11(d,J＝8.2Hz,1H),7.77(dd,J＝1.6,8.2Hz,1H),7.90(d,J＝1.2Hz,1H)。
Production instance 18
the synthesis of 5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base)-2-(trifluoromethoxy) benzonitrile
According to the method for production instance 17-(2), thick title compound (744mg) takes from the bromo-2-of 5-(trifluoromethoxy) benzonitrile (CAS numbering 1210906-15-2; 500mg, 1.88mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.35(s,12H),7.37,(qd,J＝1.6,8.6Hz,1H),8.04(dd,J＝1.4,8.4Hz,1H),8.14(d,J＝1.6Hz,1H)。
Production instance 19
2-(3-((methoxymethoxy) methyl)-4-(trifluoromethoxy) phenyl)-4,4,5,5-tetramethyl-s-1,3,2-bis- the synthesis of oxa-ring pentaborane
(1) the synthesis of the bromo-2-of 4-((methoxymethoxy) methyl)-1-(trifluoromethoxy) benzene
Under ice-cooling, to (the bromo-2-of 5-(trifluoromethoxy) phenyl) methyl alcohol (CAS numbering 685126-86-7; 5.00g, 18.4mmol) and the solution of DIPEA (9.64mL, 55.3mmol) in DCM (50mL) in add Chloromethyl methyl ether (2.80mL, 36.9mmol).This reaction mixture is stirred 30 minutes under ice-cooling, then heats to room temperature, and stir 13 hours.Water is added, to be separated this organic layer in this reaction mixture.Organic over anhydrous magnesium sulfate is carried out drying and then under reduced pressure concentrates.The resistates of this generation is carried out purifying, to obtain title compound (5.60g, 17.8mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):3.42(s,3H),4.63(s,2H),4.74(s,2H),7.12(dd,J＝1.6,9.0Hz,1H)7.44(dd,J＝2.5,8.8Hz,1H)7.70(d,J＝2.0Hz,1H)。
(2) synthesis of 2-(3-((methoxymethoxy) methyl)-4-(trifluoromethoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes
According to the method for production instance 17-(2), thick title compound (1.66g) is obtained from the compound (1.12g, 3.56mmol) obtained in production instance 19-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):1.34(s,12H),3.43(s,3H),4.66(s,2H),4.74,(s,2H),7.24(qd,J＝2.0,8.2Hz,1H),7.78(dd,J＝1.6,8.2Hz,1H),7.95(d,1.6Hz,1H)。
Production instance 20
2-(the chloro-3-of 4-((methoxymethoxy) methyl) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxane penta boron the synthesis of alkane
According to the method for production instance 17-(2), title compound (3.36g, 10.8mmol) is obtained from the chloro-2-of the bromo-1-of 4-((methoxymethoxy) methyl) benzene (CAS numbering 790228-98-7; 3.95g, 14.9mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.34(s,12H),3.48(s,3H),4.69(s,2H),4.76(s,2H),7.37(d,J＝7.8Hz,1H),7.67(dd,J＝1.6,7.8Hz,1H),7.89(d,J＝1.5Hz,1H)。
Production instance 21
2-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes synthesis
According to the method for production instance 17-(2), title compound (4.58g, 14.4mmol) is obtained from the bromo-2-methoxyl group of 4--1-(trifluoromethoxy) benzene (CAS numbering 672948-65-1; 5.23g, 19.7mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.35(s,12H),3.92,(s,3H),7.23(qd,J＝1.2,8.2Hz,1H),7.40(m,2H)。
Production instance 22
the conjunction of 2-(the chloro-3-of 4-(methoxymethoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes become
(1) the synthesis of the chloro-2-of the bromo-1-of 4-(methoxymethoxy) benzene
To bromo-2-chlorophenol (the CAS numbering 183802-98-4 of 5-; 1.00g, 4.82mmol), add Chloromethyl methyl ether (0.44mL, 5.78mmol) in the mixture of salt of wormwood (2.00g, 14.5mmol) and acetone (15.0mL).At room temperature this reaction mixture is stirred 2 hours.Water and ethyl acetate is added, to be separated this organic layer in this reaction mixture.Organic layer washs with water and with saturated water-based sodium chloride solution continuously, and uses anhydrous magnesium sulfate drying.Under reduced pressure this filtrate is concentrated and the resistates of this generation is carried out purifying, to obtain title compound (1.20g, 4.77mmol) by silica gel chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz，CDCl3)δ(ppm):3.52(s,3H),5.23(s,2H),7.08(dd,J＝2.2,8.4Hz,1H),7.25(d,J＝9.8Hz,1H),7.34-7.38(m,2H),7.53(s,1H)。
(2) synthesis of 2-(the chloro-3-of 4-(methoxymethoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes
According to the method for production instance 17-(2), title compound (688mg, 2.30mmol) is obtained from the compound (1.20g, 4.77mmol) obtained in production instance 22-(1).
1H-NMR(400MHz，CDCl3)δ(ppm):1.34(s,12H),3.54(s,3H),5.29(s,2H),7.34-7.38(m,2H),7.53(s,1H)
Production instance 23
(2-(methylol)-6-picoline-4-base) borate hydrochlorate
(6-picoline-2-base) methyl acetate (CAS numbering 13287-64-4 will be comprised at TBME (9.08mL); 839mg, 5.08mmol), two (pinacol ester) two boron (1.29g, 5.08mmol), two (1,5-cyclooctadiene) two-μ-methoxyl group two iridium (I) (337mg, 0.508mmol) He 4, the solution of 4'-bis--tert-butyl-2,2'-bis-pyridine (136mg, 0.508mmol) stirs 30 minutes at 80 DEG C under microwave radiation.This reaction mixture is cooled to room temperature and then vapourisation under reduced pressure.This resistates is dissolved in THF (15.1mL), and adds 5N hydrochloric acid (5.08mL) to this mixture.By the solution stirring 48 hours of this generation, and THF vapourisation under reduced pressure.The solution of this generation is used diethyl ether four times and then under reduced pressure concentrates.The solid of this generation is used DCM washing, to obtain title compound (514mg, 2.53mmol).
1H-NMR(400MHz,MeOH-d4)δ(ppm):2.78(brs,3H),4.93(brs,2H),7.95(brs,1H),8.03(brs,1H)。
Production instance 24
2-(((tert-butyl dimetylsilyl) oxygen base) methyl)-6-methyl-4-(4,4,5,5-tetramethyl--1,3,2- dioxaborolanes-2-base) synthesis of pyridine
(1) 2-(((tert-butyl dimethylfirst silylation) oxygen base) methyl)-6-picolinesynthesis
Under ice-cooling, to 6-methyl-2-piconol (CAS numbering 1122-71-0; 3.00g, 24.4mmol) add imidazoles (2.16g, 31.7mmol) and TBSCl (4.04g, 26.8mmol) continuously in solution in DMF (50mL), and this mixture is at room temperature stirred 30 minutes.Water and normal heptane is added, to be separated this organic layer in this reaction mixture.Used by this organic layer saturated water-based sodium chloride solution to carry out washing and using anhydrous magnesium sulfate drying, and under reduced pressure concentrate.The resistates of this generation is carried out purifying, to obtain title compound (4.70g, 19.8mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):0.12(s,6H),0.96(s,9H),2.52(s,3H),4.81(s,2H),7.00(d,J＝7.7Hz,1H),7.32(d,J＝7.7Hz,1H),7.59(t,J＝7.7Hz,1H)。
(2) synthesis of 2-(((tert-butyl dimetylsilyl) oxygen base) methyl)-6-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine
Compound (the 2.00g that will obtain in production instance 24-(1), 8.42mmol), two (pinacol ester) two boron (2.14g, 8.42mmol), two (1,5-cyclooctadiene) two-μ-methoxyl group two iridium (I) (168mg, 0.253mmol) with 4.4'-bis--tert-butyl-2, the mixture of 2'-bis-pyridine (68mg, 0.253mmol) in TBME (20mL) stirs 1.5 hours at 85 DEG C.This reaction mixture is cooled to room temperature and then vapourisation under reduced pressure.The resistates of this generation is used silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) purifying twice, to obtain title compound (450mg, 1.24mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.12(s,6H),0.96(s,9H),1.35(s,12H),2.52(s,3H),4.82(s,2H),7.37(s,1H),7.63(s,1H)。
Example 1
(R)-6-methyl-5,6,8,9-imidazolidine also for-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) the synthesis of 2-(the chloro-3-Methoxybenzamido of 4-) acetic acid
By chloro-for 4-3-methoxybenzoic acid (CAS numbering 85740-98-3; 25.0g, 134mmol), thionyl chloride (19.6mL, 268mmol), and the mixture of DMF (1.04mL) in toluene (428mL) 110 DEG C stir 2 hours.This reaction mixture is cooled to room temperature and then by this solvent vapourisation under reduced pressure to obtain thick chloride of acid.The thick chloride of acid generated is dissolved in the THF of sufficient quantity, and adds glycine (CAS numbering 56-40-6 in this mixture; 17.93g, 161mmol).At room temperature, 3N aqueous sodium hydroxide solution (134mL) is slowly added into this mixture, and this reaction mixture is at room temperature stirred 2 hours.Use hydrochloric acid to carry out acidifying to this reaction mixture, and add ethyl acetate.This organic layer is separated and the organic layer of generation is washed with water and saturated water-based sodium chloride solution continuously.Organic over anhydrous dried over mgso.This organic layer is under reduced pressure concentrated to obtain title compound (31.1g, 128mmol).
1H-NMR(400MHz,MeOH-d4)δ(ppm):3.94-3.97(m,3H),4.07-4.12(m,2H),7.40-7.49(m,2H),7.54-7.56(m,1H),8.81(brs,1H)。
(2) 2-(4-chloro-3-p-methoxy-phenyl) oxazole-5 (4H)-onesynthesis
The compound (30.5g, 125mmol) obtained in example 1-(1) and the solution of NMM (14.5mL, 131mmol) in THF (300mL) are cooled to-10 DEG C.At that same temperature, dropwise in this reaction soln, methyl-chloroformate (10.2mL, 131mmol) is added.After having added, this reaction mixture is slowly heated to room temperature and at room temperature stirs 1 hour further.The insolubles of generation is filtered out and this filtrate is under reduced pressure concentrated.The solid of this generation is used normal heptane washing, to obtain title compound (24.3g, 108mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):3.97(s,3H),4.43(s,2H),7.45-7.55(m,3H)。
(3) (R)-methyl 3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] synthesis of [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
Compound (the 1.90g that will obtain in production instance 1-(6), 13.3mmol) and at the solution of the middle compound obtained of example 1-(2) (3.0g, 13.3mmol) in THF (24mL) heat and stir 2 hours at 150 DEG C under microwave radiation.This mixture is under reduced pressure concentrated, and the resistates of this generation is dissolved in (30mL) in methyl alcohol.In this reaction mixture, add sodium methylate (718mg, 13.3mmol) and resultant is stirred 1 hour at 100 DEG C.This reaction mixture is cooled to room temperature, and adds water and ethyl acetate.By this organic layer be separated and continuous water and saturated water-based sodium chloride solution wash.Organic over anhydrous dried over mgso.By this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain title compound (3.47g, 9.89mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.22(d,J＝6.3Hz,3H),3.06-3.14(m,1H),3.60-3.75(m,2H),3.90(s,3H),3.94(s,3H),3.93-3.99(m,1H),4.06(dd,J＝4.7,16.4Hz,1H),4.17-4.24(m,2H),6.87(dd,J＝2.0,8.2Hz,1H),7.16(d,J＝2.0Hz,1H),7.43(d,J＝8.2Hz,1H)。
(4) (R) the bromo-3-of-1-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] synthesis of [Isosorbide-5-Nitrae] oxygen azatropylidene
The compound (3.47g, 9.89mmol) that will obtain in example 1-(3) and the solution of 5N aqueous sodium hydroxide solution (9.9mL, 49.5mmol) in methyl alcohol (20mL) stir 2 hours at 100 DEG C.This reaction mixture is cooled to room temperature and uses 5N hydrochloric acid to carry out acidifying.This mixture is under reduced pressure concentrated.DMF (20mL), salt of wormwood (2.32g, 16.8mmol) is added to this resistates, and NBS (1.99g, 11.2mmol), and this mixture is at room temperature stirred 8 hours.Water-based hypo solution and ethyl acetate is added in this reaction mixture.By this organic layer be separated and continuous water and saturated water-based sodium chloride solution wash.By this organic over anhydrous dried over mgso, and under reduced pressure this solvent is evaporated.The resistates of this generation is carried out purifying, to obtain title compound (2.42g, 6.51mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.23(d,J＝6.6Hz,3H),2.93-3.11(m,2H),3.57-3.74(m,2H),3.89-3.97(m,1H),3.94(s,3H),4.14-4.26(m,2H),6.85(dd,J＝2.0,8.2Hz,1H),7.15(d,J＝2.0Hz,1H),7.43(d,J＝8.2Hz,1H)。
(5) (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (570mg, 1.53mmol), 2,6-dimethyl-pyridine-4-boric acid (the CAS numbering 846548-44-5 that will obtain in example 1-(4); 463mg, 3.07mmol), tetrakis triphenylphosphine palladium (0) (89mg, 0.077mg), the mixture of water-based sodium carbonate solution (2M, 2.3mL) and DME (8mL) stirs 1 hour at 150 DEG C under microwave radiation.Water and ethyl acetate is added in this mixture.This organic layer is separated, with anhydrous magnesium sulfate drying, and then under reduced pressure concentrates.The resistates of this generation is carried out purifying, to obtain title compound (388mg, 0.975mmol) by silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.6Hz,3H),2.56(s,6H),3.19(ddd,J＝2.4,10.6,16.0Hz,1H),3.37(dd,J＝3.9,16.0Hz,1H),3.63-3.70(m,1H),3.75-3.82(m,1H),3.94-4.01(m,1H),3.97(s,3H),4.19-4.28(m,2H),6.93(dd,J＝2.0,8.2Hz,1H),7.18(d,J＝2.0Hz,1H),7.21(s,2H),7.46(d,J＝8.2Hz,1H)。
ESI-MS m/z 398[M+H]+
Example 2
1-(2,6-lutidine-4-base)-3-(the fluoro-4-of 3-(2,2,2-trifluoro ethoxy) phenyl)-5,6,8,9-tetrahydrochysenes the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) 2-(the synthesis of 4-benzyloxy-3-fluorophenyl) oxazole-5 (4H)-one
According to the method for example 1-(1) and 1-(2), title compound (1.58g, 5.54mmol) is obtained from 4-benzyloxy-3-fluorobenzoate (CAS numbering 152552-64-2; 2.00g, 8.12mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):4.39(s,2H),5.22(s,2H),7.03-7.09(m,1H),7.33-7.48(m,5H),7.67-7.78(m,2H)。
(2) 3-(4-(benzyloxy)-3-fluorophenyl)-1-(2,6-lutidine-4-base)-5,6,8,9-tetrahydrochysene miaows the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to example 1-(3), the method of 1-(4) and 1-(5), title compound (0.112g, 0.253mmol) be obtained from the compound (1.10g, 3.87mmol) obtained in example 2-(1) and 5-methoxyl group-2,3,6,7-tetrahydrochysene-Isosorbide-5-Nitrae-oxygen azatropylidene (0.500g, 3.87mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.55(s,6H),3.27(dd,J＝3.7,5.7Hz,2H),3.89(td,J＝4.3,9.0Hz,4H),4.22-4.29(m,2H),5.20(s,2H),7.04-7.10(m,1H),7.15-7.22(m,3H),7.27-7.46(m,6H)。
(3) 4-(1-(2,6-lutidine-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine zhuo-3-base) synthesis of-2-fluorophenol
Under a hydrogen atmosphere at room temperature, by the compound (105mg obtained in example 2-(2) in ethanol (2.00mL), 0.237mmol), 5% palladium/carbon (25.2mg, comprise 50% water-content), and the suspension agitation 4 hours of acetic acid (0.014mL, 0.237mmol).These insolubless are removed, then this filtrate is under reduced pressure concentrated and the resistates generated is carried out purifying, to obtain title compound (71.0mg, 0.201mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.55(s,6H),3.26(dd,J＝3.9,5.5Hz,2H),3.86-3.91(m,4H),4.22-4.29(m,2H),6.90-6.97(m,1H),7.05(d,J＝8.6Hz,1H),7.14-7.23(m,1H),7.21(s,2H)。
ESI-MS m/z 354[M+H]+
(4) 1-(2,6-lutidine-4-base)-3-(the fluoro-4-of 3-(2,2,2-trifluoro ethoxy) phenyl)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
To the compound (14.0mg obtained in example 2-(3), 0.040mmol), salt of wormwood (16.4mg, 0.119mmol) and in the mixture of DMF (500 μ L) add 2-iodo-1,1,1-Halothane (16.6mg, 0.079mmol).This reaction mixture is stirred 3 hours at 100 DEG C.This reaction mixture is cooled to room temperature, and adds water and ethyl acetate.This organic layer is separated, continuous water and with the washing of saturated water-based sodium chloride solution, and uses anhydrous magnesium sulfate drying.The resistates of this generation is carried out purifying, to obtain title compound (4.88mg, 0.011mmol) by silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.28(dd,J＝3.7,5.7Hz,2H),3.84-3.95(m,4H),4.23-4.31(m,2H),4.45-4.52(m,2H),7.09-7.16(m,1H),7.19(s,2H),7.26-7.29(m,1H),7.35(dd,J＝2.2,11.5Hz,1H)。
ESI-MS m/z 436[M+H]+
Example 3
3-(the chloro-3-of 4-(2,2,2-trifluoro ethoxy) phenyl)-1-(2,6-lutidine-4-base)-5,6,8,9-tetrahydrochysenes the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) the bromo-3-of 1-(the chloro-3-p-methoxy-phenyl of 4-)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine tall and erect synthesis
According to the method for example 1-(3) and 1-(4), title compound (73.0mg, 0.204mmol) be obtained from the compound (873mg obtained in example 1-(2), 3.87mmol) with 5-methoxyl group-2,3,6,7-tetrahydrochysene-1,4-oxygen azatropylidene (0.500g, 3.87mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):3.00-3.08(m,2H),3.79-3.90(m,4H),3.94(s,3H),4.22-4.28(m,2H),6.87(dd,J＝1.8,8.0Hz,1H),7.17(d,J＝1.6Hz,1H),7.41(d,J＝8.2Hz,1H)。
(2) 5-(bromo-5,6,8, the 9-imidazolidines of 1-are [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base also)-2-chlorophenol synthesis
Compound (the 68.0mg that will obtain in example 3-(1), solution 0.190mmol) in DCM (3.00mL) is cooled to-78 DEG C, and drip the 1M Boron tribromide solution (0.951mL, 0.951mmol) in DCM.This reaction mixture is slowly heated to room temperature, and adds ammonia soln.Chloroform is added, to be separated this organic layer in this mixture.This organic layer is washed with water and with saturated water-based sodium chloride solution continuously, and then uses anhydrous magnesium sulfate drying.The resistates of this generation is carried out purifying, to obtain title compound (41.2mg, 0.120mmol) by silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):3.00-3.07(m,2H),3.78-3.90(m,4H),4.20-4.27(m,2H),6.88(dd,J＝2.0,8.2Hz,1H),7.24(d,J＝2.0Hz,1H),7.36(d,J＝8.2Hz,1H)。
(3) the bromo-3-of 1-(the chloro-3-of 4-(2,2,2-trifluoro ethoxy) phenyl)-5,6,8,9-imidazolidine also [1,5- d] synthesis of [Isosorbide-5-Nitrae] oxygen azatropylidene
To the compound (38.1mg obtained in example 3-(2), 0.111mmol), salt of wormwood (61.3mg, 0.444mmol) and in the mixture of DMF (1.00mL) add 3-iodo-1,1,1-Halothane (69.8mg, 0.333mmol).This reaction mixture is cooled to room temperature, and adds water and ethyl acetate.This organic layer is separated, continuous water and with the washing of saturated water-based sodium chloride solution, and uses anhydrous magnesium sulfate drying.The resistates of this generation is carried out purifying, to obtain title compound (31.1mg, 0.073mmol) by silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):3.01-3.10(m,2H),3.80-3.92(m,4H),4.22-4.30(m,2H),4.44-4.50(m,2H),7.02(dd,J＝2.0,8.2Hz,1H),7.21(d,J＝1.8Hz,1H),7.47(d,J＝8.2Hz,1H)。
(4) 3-(the chloro-3-of 4-(2,2,2-trifluoro ethoxy) phenyl)-1-(2,6-lutidine-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (7.20mg, 0.016mmol) be obtained from the compound (31.0mg obtained in example 3-(3), 0.073mmol) He 2,6-dimethyl-pyridine-4-boric acid (22.0mg, 0.146mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.28(dd,J＝3.9,5.5Hz,2H),3.84-3.95(m,4H),4.24-4.31(m,2H),4.45-4.52(m,2H),7.09(dd,J＝1.8,8.4Hz,1H),7.19(s,2H),7.25(d,J＝1.6Hz,1H),7.50(d,J＝8.2Hz,1H)。
ESI-MS m/z 452[M+H]+
Example 4
3-(the bromo-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-5,6,8,9-imidazolidine also [1,5- d] synthesis of [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) methyl 3-(3-methoxyl group-4-nitrophenyl)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen the synthesis of azatropylidene-1-carboxylicesters
3-methoxyl group-4-nitrobenzoic acid (CAS numbering 5081-36-7 is obtained from according to the method ， azolactone compound of example 1-(1) and 1-(2); 3.88g, 19.7mmol).According to the method for example 1-(3), title compound (1.20g, 3.46mmol) Huo Qu Zi azolactone compound (3.36g, 14.2mmol) with 5-methoxyl group-2,3,6,7-tetrahydrochysene-Isosorbide-5-Nitrae-oxygen azatropylidene (1.82g, 14.2mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):3.60-3.66(m,2H),3.82-3.86(m,2H),3.87-3.93(m,2H),3.92(s,3H),4.02(s,3H),4.26-4.31(m,2H),7.02(dd,1.4,8.0Hz,1H),7.39(d,J＝1.6Hz,1H),7.93(d,J＝8.2Hz,1H)。
(2) the bromo-3-of 1-(3-methoxyl group-4-nitrophenyl)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen nitrogen assorted tall and erect synthesis
According to the method for example 1-(4), title compound (83.4mg, 0.227mmol) is obtained from the compound (111mg, 0.320mmol) obtained in example 4-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):3.08(dd,J＝4.3,5.9Hz,2H),3.86(td,J＝4.2,8.0Hz,4H),4.02(s,3H),4.27-4.32(m,2H),7.00(dd,J＝1.6,8.6Hz,1H),7.38(d,J＝1.6Hz,1H),7.92(d,J＝8.6Hz,1H)。
ESI-MS m/z 368,370[M+H]+390,392[M+Na]+
(3) 1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-nitrophenyl)-5,6,8,9-tetrahydrochysene miaows the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), thick title compound (101mg) is obtained from the compound (83mg obtained in example 4-(2), 0.23mmol) with 2,6-dimethyl-pyridine-4-boric acid (68mg, 0.45mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.57(s,6H),3.30(dd,J＝3.9,5.5Hz,2H),3.88-3.95(m,4H),4.04(s,3H),4.30-4.36(m,2H),7.07(dd,1.6,8.2Hz,1H),7.20(s,2H),7.42(d,J＝1.6Hz,1H),7.96(d,J＝8.6Hz,1H)。
ESI-MS m/z 395[M+H]+
(4) 4-(1-(2,6-lutidine-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine zhuo-3-base) synthesis of-2-anisidine
Under a hydrogen atmosphere, the solution stirring 6 hours of the compound (101mg) that will obtain in the example 4-(3) and the palladium/carbon (20mg comprises the water-content of 50%) of 10% (1.0mL) in ethanol.This reaction soln is filtered by Celite (trade mark) and then filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (39.8mg, 0.109mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.53(s,6H),3.22-3.32(m,2H),3.80-3.94(m,4H),3.89(s,3H),3.99(brs,2H),4.23-4.34(m,2H),6.73(d,J＝7.8Hz,1H),6.82(dd,J＝1.8,8.0Hz,1H),7.02(d,J＝2.1Hz,1H),7.21(s,2H)。
ESI-MS m/z 365[M+H]+
(5) 3-(the bromo-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-5,6,8,9-imidazolidines and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Under ice-cooling, to the compound (20mg obtained in example 4-(4), 0.055mmol), in water (0.10mL) and the solution of concentrated sulfuric acid (0.10mL) in acetonitrile, (0.40mL) adds water-based sodium nitrite solution (1.0M, 0.11mL).At that same temperature this mixture is stirred 10 minutes, then add water-based cupric bromide (I) solution (2.0M, 0.22mL) and this mixture is stirred 1 hour.This reaction mixture be heated to 50 DEG C and stir 5 hours, and being then cooled to room temperature.In this reaction mixture, add ethyl acetate, use ammonia scrubbing twice, and use saturated water-based sodium chloride solution to wash.The organic over anhydrous dried over sodium sulfate of generation is also under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain this title compound (16mg, 0.037mmol) by silicon thin-layer chromatography (ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.55(s,6H),3.27(dd,J＝3.9,5.5Hz,2H),3.84-3.93(m,4H),3.95(s,3H),4.25-4.30(m,2H),6.87(dd,J＝2.0,8.2Hz,1H),7.16(d,J＝2.0Hz,1H),7.20(s,2H),7.62(d,J＝7.8Hz,1H)。
ESI-MS m/z 428,430[M+H]+
Example 5
(R)-1-(2,6-lutidine-4-base)-3-(the fluoro-3-of 4-(2-fluorine oxyethyl group) phenyl)-6-methyl-5,6,8,9- the synthesis of imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) the fluoro-3-of 4-(methoxymethoxy) benzoic synthesis
Under ice-cooling, to fluoro-3-hydroxy-benzoic acid (the CAS numbering 51446-31-2 of 4-; 10.0g, 64.1mmol) and the solution of TEA (35.7mL, 256mmol) in THF (150mL) in add Chloromethyl methyl ether (14.5mL, 192mmol) and at room temperature this reaction mixture stirred 2 hours.In this reaction mixture, add 1N hydrochloric acid and ethyl acetate, this organic layer is separated, and the organic layer be separated is filtered by silicagel pad (silica gel, ethyl acetate/normal heptane).By the filtrate vapourisation under reduced pressure generated.The resistates of generation is dissolved in methyl alcohol (100mL), adds 5N aqueous sodium hydroxide solution (38.4mL), and this mixture is stirred 1 hour at 80 DEG C.This reaction mixture is cooled to room temperature, and adds 5N hydrochloric acid and ethyl acetate in this reaction mixture, to be separated this organic layer.This organic layer is washed with water and with saturated water-based sodium chloride solution continuously, and uses anhydrous magnesium sulfate drying.By this solvent vapourisation under reduced pressure, to obtain thick title compound (10.1g).
1H-NMR(400MHz,CDCl3)δ(ppm):3.54(s,3H),5.28(s,2H),7.13-7.22(m,1H),7.78(ddd,J＝2.0,4.5,8.4Hz,1H),7.93(dd,J＝2.0,7.8Hz,1H)。
(2) benzyl 2-(the fluoro-3-of 4-(methoxymethoxy)) benzamido) synthesis of acetic ester
Under ice-cooling, to the compound (8.90g), glycine benzyl ester p-toluenesulfonic esters (the CAS numbering 28607-46-7 that obtain in example 5-(1) in DCM (100mL); 19.5g; 57.8mmol), HOBT (7.81g, 57.8mmol), and add EDC (11.1g, 57.8mmol) in the solution of TEA (16.1mL, 116mmol).This reaction mixture is stirred and spends the night, and then add 1N hydrochloric acid and chloroform.This organic layer is separated, continuous water and with the washing of saturated water-based sodium chloride solution, and uses anhydrous magnesium sulfate drying.Under reduced pressure this filtrate is concentrated and the resistates of this generation is carried out purifying, to obtain title compound (14.2g, 40.9mmol) by silica gel chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):3.52(s,3H),4.27(d,J＝5.1Hz,2H),5.23(s,2H),5.26(s,2H),6.61(brs,1H),7.14(dd,J＝8.4,10.4Hz,1H),7.30-7.51(m,6H),7.68(dd,J＝2.2,8.0Hz,1H)。
(3) the synthesis of 2-(the fluoro-3-of 4-(methoxymethoxy) benzamide) acetic acid
Under a hydrogen atmosphere at room temperature, by the compound (14.2g obtained in example 5-(2) in ethanol (100mL), the suspension agitation of the palladium/carbon (0.44g comprises the water-content of 50%) of 40.9mmol) He 5% 30 minutes.Remove palladium catalyst by this solvent vapourisation under reduced pressure, to obtain thick title compound (10.3g).
1H-NMR(400MHz,MeOH-d4)δ(ppm):3.51(s,3H),4.02-4.12(m,2H),5.27(s,2H),7.21(dd,J＝8.4,10.7Hz,1H),7.51-7.54(m,1H),7.75(dd,J＝2.2,8.0Hz,1H)。
(4) 2-(the synthesis of the fluoro-3-of 4-(methoxymethoxy) phenyl) oxazole-5 (4H)-one
According to the method for example 1-(2), title compound (9.11g, 26.7mmol) is obtained from the compound (10.3g) obtained in example 5-(3).
1H-NMR(400MHz,CDCl3)δ(ppm):3.54(s,3H),4.42(s,2H),5.28(s,2H),7.20(dd,J＝8.5,10.5Hz,1H),7.63(ddd,J＝2.1,4.4,8.5Hz,1H),7.84(dd,J＝2.1,7.9Hz,1H)。
(5) (R) the bromo-3-of-1-(the fluoro-3-of 4-(methoxymethoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(3) and 1-(4), title compound (388.0mg, 1.01mmol) be obtained from the compound (1.50g obtained in example 5-(4), 6.27mmol) and the compound (0.898g, 6.27mmol) obtained in the production instance 1-(6).
1H-NMR(400MHz,CDCl3)δ(ppm):1.23(d,J＝6.6Hz,3H),2.93-3.10(m,2H),3.52(s,3H),3.58-3.65(m,1H),3.68-3.76(m,1H),3.90(dd,J＝8.4,14.7Hz,1H),4.14-4.24(m,2H),5.22-5.28(m,2H),7.03-7.07(m,1H),7.16(dd,J＝8.4,10.6Hz,1H),7.32(dd,J＝2.1,7.8Hz,1H)。
(6) (R)-1-(2,6-lutidine-4-base)-3-(the fluoro-3-of 4-(2-methoxymethoxy) phenyl)-6- methyl-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (78mg, 0.190mmol) is obtained from the compound (330mg, 0.857mmol) obtained in example 5-(5).
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.4Hz,3H),2.55(s,6H),3.12-3.22(m,1H),3.32-3.38(m,1H),3.53(s,3H),3.63-3.68(m,1H),3.76-3.83(m,1H),3.92-3.98(m,1H),4.18-4.27(m,2H),5.24-5.30(m,2H),7.09-7.13(m,1H),7.17-7.22(m,3H),7.36(dd,J＝2.0,7.8Hz,1H)。
(7) (R)-5-(1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base) synthesis of-2-fluorophenol hydrochloride
In the solution of the compound (78mg, 190 μm of ol) obtained in the example 5-(6) in methyl alcohol, add 4N hydrochloric acid (0.474mL, 1.90mmol) and this mixture is stirred 4 hours at 80 DEG C.This reaction mixture is cooled to room temperature and by this solvent vapourisation under reduced pressure, to obtain thick title compound (68mg).
1H-NMR(400MHz,MeOH-d4)δ(ppm):1.26(d,J＝6.3Hz,3H),2.84(s,6H),3.35-3.39(m,1H),3.46-3.51(m,1H),3.74-3.86(m,1H),4.00(t＝6.8Hz,1H),4.22-4.25(m,1H),4.35-4.45(m,2H),7.21(ddd,J＝2.3,4.1,8.4Hz,1H),7.29-7.48(m,2H),7.95(s,2H)。
(8) (R)-1-(2,6-lutidine-4-base)-3-(the fluoro-3-of 4-(2-fluorine oxyethyl group) phenyl)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
To the compound (30.0mg obtained in example 5-(7), 0.074mmol), salt of wormwood (30.8mg, 0.223mmol), 2-fluoro ethyl tosylate (24.3mg, 0.111mmol) is added with in the mixture of DMF (300 μ L).This reaction mixture is stirred 3 hours at 80 DEG C.This reaction mixture is cooled to room temperature, and adds water and ethyl acetate.This organic layer is separated, continuous water and with the washing of saturated water-based sodium chloride solution, and uses anhydrous magnesium sulfate drying.The resistates of this generation is carried out purifying, to obtain title compound (24.3mg, 0.059mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):1.24-1.27(m,3H),2.55(s,6H),3.11-3.23(m,1H),3.36(dd,J＝4.3,16.0Hz,1H),3.60-3.82(m,2H),3.96(dd,J＝8.4,15.0Hz,1H),4.17-4.27(m,2H),4.29-4.44(m,2H),4.69-4.89(m,2H),7.00-7.02(m,1H),7.14-7.25(m,4H)。
ESI-MS m/z 414[M+H]+
Example 6
(R)-3-(3-cyclo propyl methoxy-4-fluorophenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9- the synthesis of imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-5-(1-bromo-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base also)- the synthesis of 2-fluorophenol hydrochloride
The solution of compound (170mg, 0.441mmol) in 4M hydrogenchloride/methyl alcohol (1.10mL, 4.41mmol) that will obtain in example 5-(5) stirs 2 hours at 80 DEG C.This reaction mixture is cooled to room temperature and by this solvent vapourisation under reduced pressure, to obtain thick title compound (166mg).
1H-NMR(400MHz,MeOH-d4)δ(ppm):1.21(d,J＝6.6Hz,3H),3.07-3.16(m,2H),3.62-3.69(m,1H),3.83-3.89(m,1H),4.13-4.20(m,2H),4.25-4.36(m,1H),7.05-7.10(m,1H),7.19(d,J＝8.2Hz,1H),7.31-7.39(m,1H)。
(2) (R) the bromo-3-of-1-(3-(cyclo propyl methoxy)-4-fluorophenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
To the compound (50.0mg obtained in example 6-(1), 0.132mmol), salt of wormwood (110mg, 0.794mmol) and in the mixture of DMF (400 μ L) add ring third monobromomethane (64.2 μ L, 0.662mmol), and by this mixture 120 DEG C stir 5 hours.This reaction mixture is cooled to room temperature, and adds water and ethyl acetate.This organic layer is separated, continuous water and with the washing of saturated water-based sodium chloride solution, and uses anhydrous magnesium sulfate drying.The resistates of this generation is carried out purifying, to obtain title compound (20.8mg, 0.053mmol) by silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):0.28-0.42(m,2H),0.59-0.75(m,2H),1.13-1.25(m,3H),1.26-1.40(m,1H),2.87-3.13(m,2H),3.51-3.74(m,2H),3.84-3.96(m,3H),4.10-4.27(m,2H),6.85(ddd,J＝2.0,4.2,8.3Hz,1H),7.07-7.20(m,2H)。
(3) (R)-3-(3-cyclo propyl methoxy-4-fluorophenyl)-1-(2,6-lutidine-4-base)-6-first base-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (6.80mg, 0.016mmol) be obtained from the compound (19.5mg obtained in example 6-(2), 0.049mmol) He 2,6-dimethyl-pyridine-4-boric acid (8.94mg, 0.059mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.29-0.42(m,2H),0.62-0.73(m,2H),1.25(d,J＝6.3Hz,3H),1.28-1.38(m,1H),2.55(s,6H),3.19(dd,J＝2.3,10.5Hz,1H),3.35(dd,J＝3.9,16.0Hz,1H),3.60-3.82(m,2H),3.88-4.01(m,3H),4.17-4.28(m,2H),6.93(ddd,J＝2.3,4.1,8.4Hz,1H),7.11-7.23(m,4H)。
ESI-MS m/z 422[M+H]+
Example 7
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) the synthesis of 2-(3-methoxyl group-4-(trifluoromethyl) benzamido) acetic acid
Under ice-cooling, to 3-methoxyl group-4-(trifluoromethyl) phenylformic acid (CAS numbering 276861-63-3; 20.5g, 93.1mmol) and the suspension of DMF (0.205mL, 2.65mmol) in THF (41mL)/DCM (164mL) in dropwise add oxalyl chloride (9.59mL, 112mmol).This reaction mixture is heated to room temperature and stirs 2 hours further.By this solvent vapourisation under reduced pressure, to obtain chloride of acid thick accordingly.Under ice-cooling; the mixture back warp time of 15 minutes to glycine (8.39g, 112mmol), 2N aqueous sodium hydroxide solution (93mL) and THF (200mL) dropwise adds the solution of thick chloride of acid in THF (40mL).This reaction mixture is at room temperature stirred 3 days.Under ice-cooling, 5N hydrochloric acid is used to carry out acidifying to this reaction mixture.Ethyl acetate is added, to be separated this organic layer in this mixture.By the organic over anhydrous dried over mgso generated, and this solvent of vapourisation under reduced pressure, to obtain title compound (25.6g, 92.0mmol).
1H-NMR(400MHz,DMSO-d6)δ(ppm):3.94(s,2H),3.96(s,3H),7.57(d,J＝8.2Hz,1H),7.67(s,1H),7.75(d,J＝8.2Hz,1H),9.05(brs,1H)。
(2) 2-(the synthesis of 3-methoxyl group-4-(trifluoromethyl) phenyl) oxazole-5 (4H)-one
At-10 DEG C to the compound (8.00g obtained in example 7-(1) in THF (150mL), 28.9mmol) with NMM (3.33mL, methyl-chloroformate (2.34mL, 30.3mmol) is added in solution 30.3mmol).This reaction mixture is stirred 1 hour at-10 DEG C and then stirs and within 2 hours, it is slowly heated to room temperature simultaneously.The solid generated is passed through Celite (trade mark) filtering separation.This filtrate is under reduced pressure concentrated, to obtain title compound (7.48g, 28.9mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):3.95(s,3H),4.44(s,2H),7.32-7.39(m,1H),7.58-7.63(m,3H)。
(3) (R)-methyl 3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
Will at example 7-(2) (4.16g, the compound obtained 16.1mmol) and the solution of compound in toluene (25mL) obtained in production instance 1-(6) (2.00g, 14.0mmol) heat 6 hours under reflux.This reaction mixture is cooled to room temperature and by this solvent vapourisation under reduced pressure.The resistates of generation is dissolved in methyl alcohol (30mL).In this mixture, add sodium methylate (755mg, 14.0mmol), then this resultant is heated under reflux.After 3 hours, this reaction mixture is cooled to room temperature and adds ethyl acetate and saturated aqueous ammonium chloride solution.This organic layer is separated, uses saturated water-based sodium chloride solution to carry out washing and using anhydrous magnesium sulfate drying.By insolubles by filtering separation, and this filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (3.18g, 8.27mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.24(d,J＝6.6Hz,3H),3.11(ddd,J＝2.4,10.9,16.4Hz,1H),3.61-3.74(m,2H),3.91(s,3H),3.96(s,3H),3.96-4.03(m,1H),4.07(dd,J＝4.7,16.4Hz,1H),4.17-4.25(m,2H),6.97(d,J＝8.2Hz,1H),7.25(s,1H),7.64(d,J＝8.2Hz,1H)。
ESI-MS m/z 385[M+H]+
(4) (R) the bromo-3-of-1-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
2N aqueous sodium hydroxide solution (3.31mL) is added in the solution of the compound (3.18g, 8.23mmol) obtained in the example 7-(3) in ethanol (40mL).This reaction mixture is heated 2 hours under reflux.This reaction mixture is cooled to room temperature and uses 5N hydrochloric acid to carry out acidifying.This mixture is under reduced pressure concentrated.In the resistates of this generation, add ethanol (50mL) and insolubles is separated by filtration.The filtrate of generation is under reduced pressure concentrated and is dissolved in ethanol (5mL) and DMF (50mL).In this reaction mixture, add salt of wormwood (2.86g, 20.7mmol) and NBS (2.21g, 12.4mmol), and this mixture is at room temperature stirred 14 hours.Water and ethyl acetate is added, to be separated this organic layer in this mixture.Saturated water-based sodium chloride solution is used by the organic layer of this generation to carry out washing and using anhydrous magnesium sulfate drying.By insolubles by filtering separation, and this filtrate is concentrated.This resistates is carried out purifying, to obtain title compound (2.73g, 6.74mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.24(d,J＝6.3Hz,3H),2.95-3.12(m,2H),3.57-3.65(m,1H),3.67-3.75(m,1H),3.92-4.00(m,1H),3.95(s,3H),4.16-4.28(m,2H),6.95(d,J＝8.2Hz,1H),7.24(s,1H),7.63(d,J＝8.2Hz,1H)。
ESI-MS m/z 405,407[M+H]+
(5) (R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-first base-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
The compound (900mg, 2.22mmol) that will obtain in example 7-(4), 2,6-dimethyl-pyridine-4-boric acid (402mg, 2.67mmol), (A-taPhos) 2pdCl 2(79mg, 0.111mmol), water-based sodium carbonate solution (1M, 5.55mL), and the mixture of DMF (20mL) stirs 2.5 hours at 130 DEG C.This reaction mixture is cooled to room temperature, and then in this mixture, adds ethyl acetate and water, to be separated this organic layer.Saturated water-based sodium chloride solution is used by this organic layer to carry out washing and using anhydrous magnesium sulfate drying.This organic layer is under reduced pressure concentrated.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) and NH silica gel column chromatography (normal heptane/ethyl acetate) is used by the resistates of this generation to carry out purifying continuously, to obtain title compound (750mg, 1.74mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.6Hz,3H),2.56(s,6H),3.20(ddd,J＝2.4,10.5,16.0Hz,1H),3.38(dd,J＝4.3,16.0Hz,1H),3.64-3.71(m,1H),3.76-3.84(m,1H),3.96-4.05(m,1H),3.97(s,3H),4.20-4.31(m,2H),7.03(d,J＝8.2Hz,1H),7.21(s,2H),7.28(s,1H),7.67(d,J＝8.2Hz,1H)。
ESI-MS m/z 432[M+H]+
Example 8
(R)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 7-(5), title compound (8.0mg, 0.019mmol) be obtained from the compound (18mg, 0.044mmol) obtained in example 7-(4) and 2-picoline-4-boric acid (CAS numbering 579476-63-4; 18mg, 0.13mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.6Hz,3H),2.60(s,3H),3.21(ddd,J＝2.3,10.5,16.4Hz,1H),3.38(dd,J＝3.9,15.6Hz,1H)3.64-3.72(m,1H),3.76-3.85(m,1H),3.98(s,3H),4.02(dd,J＝8.6,14.8Hz,1H),4.23(ddd,J＝2.3,4.7,12.1Hz,1H),4.28(d,J＝14.8Hz,1H),7.04(d,J＝7.8Hz,1H)7.28(s,1H),7.30(dd,J＝1.6,5.1Hz,1H),7.46(s,1H),7.67(d,J＝7.8Hz,1H),8.50(d,J＝5.1Hz,1H)。
ESI-MS m/z 418[M+H]+
Example 9
(R)-6-methyl-3-(3-methyl-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R) the bromo-6-methyl of-1--3-(3-methyl-4-(trifluoromethoxy) phenyl)-5,6,8,9-imidazolidines and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Method ， azolactone compound according to example 7-(1) and 7-(2) is obtained from 3-methyl-4-(trifluoromethoxy) phenylformic acid.According to the method for example 7-(3) and 7-(4), title compound (44.0mg, 0.151mmol) Huo Qu Zi azolactone compound (300mg, 1.16mmol) and the compound (166mg, 1.16mmol) obtained in the production instance 1-(6).
ESI-MS m/z 407[M+H]+
(2) (R)-6-methyl-3-(3-methyl-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 7-(5), title compound (7.20mg, 0.017mmol) be obtained from the compound (14.0mg obtained in example 9-(1), 0.0350mmol) with 2-picoline-4-boric acid (9.46mg, 0.069mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.3Hz,3H),2.38(s,3H),2.59(s,3H),3.13-3.25(m,1H),3.31-3.42(m,1H),3.62-3.72(m,1H),3.75-3.84(m,1H),3.95-4.04(m,1H),4.18-4.28(m,2H),7.28-7.34(m,3H),7.44-7.52(m,2H),8.47-8.52(m,1H)。
ESI-MS m/z 418[M+H]+
Example 10
(R)-1-(2,6-lutidine-4-base)-3-(4-ethyl-3-p-methoxy-phenyl)-6-methyl-5,6,8,9 ,-four the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-methyl 3-(the bromo-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] synthesis of [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 7-(1), 7-(2) and 7-(3), title compound (224mg, 0.567mmol) synthesis is from the bromo-3-methoxybenzoic acid of 4-(CAS numbering 56256-14-5).
ESI-MS m/z 395[M+H]+
(2) (R)-6-methyl-5,6,8,9-imidazolidine also for-methyl 3-(3-methoxyl group-4-ethenylphenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
Compound (the 214mg that will obtain in example 10-(1), 0.541mmol), tributylvinyl tin (0.190mL, 0.65mmol), tetrakis triphenylphosphine palladium (0) (25.0mg, 0.022mmol), and the mixture of DMF (3.00mL) 130 DEG C stir 3 hours.This reaction mixture is cooled to room temperature, then this solvent is blown into row by nitrogen concentrate and use silica gel column chromatography (normal heptane/ethyl acetate 1/1 to 0/1) to carry out purifying, to obtain thick title compound (190mg) this resistates.
ESI-MS m/z 343[M+H]+
(3) (R)-6-methyl-5,6,8,9-imidazolidine also for-methyl 3-(4-ethyl-3-p-methoxy-phenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
The crude product (182mg) of compound, the palladium/carbon (30mg comprises the water-content of 50%) of 10% that will obtain in example 10-(2), and the mixture of methyl alcohol (3.00mL) stirs under a hydrogen atmosphere.Further interpolation 10% palladium/carbon (100mg comprises 50% water-content), and this mixture is stirred 3 days under a hydrogen atmosphere.After this reaction completes, insolubles is filtered out by Celite (trade mark).By this solvent vapourisation under reduced pressure, to obtain title compound (157mg, 0.456mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.18-1.24(m,6H),2.67(q,J＝7.4Hz,2H),3.05-3.15(m,1H),3.61-3.68(m,1H),3.69-3.74(m,1H),3.86(s,3H),3.90(s,3H),3.94(dd,J＝8.4,15.0Hz,1H),4.06(dd,J＝4.7,16.4Hz,1H),4.16-4.24(m,1H),4.29(d,J＝15.2Hz,1H),6.87(dd,J＝1.6,7.4,1H),7.04(d,J＝1.6Hz,1H),7.19(d,J＝7.4Hz,1H)。
ESI-MS m/z 345[M+H]+
(4) (R)-6-methyl-5,6,8,9-imidazolidine also for the bromo-3-of-1-(4-ethyl-3-p-methoxy-phenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 7-(4), title compound (90.0mg, 0.246mmol) is obtained from the compound (157mg, 0.456mmol) obtained in example 10-(3).
1H-NMR(400MHz,CDCl3)δ(ppm):1.18-1.24(m,6H),2.67(q,J＝7.3Hz,2H),2.99(dd,J＝2.6,10.6Hz,1H),3.03-3.11(m,1H),3.62(ddd,J＝1.5,10.6,12.1Hz,1H),3.66-3.76(m,1H),3.82-3.97(m,4H),4.13-4.23(m,1H),4.31(d,J＝14.6Hz,1H),6.85(dd,J＝1.7,7.5Hz,1H),7.03(d,J＝1.5Hz,1H),7.19(d,J＝7.7Hz,1H)。
ESI-MS m/z 367[M+H]+
(5) (R)-1-(2,6-lutidine-4-base)-3-(4-ethyl-3-p-methoxy-phenyl)-6-methyl- 5,6,8,9, the synthesis of-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method (DME is used as solvent) of example 7-(5), title compound (22.8mg, 0.058mmol) is obtained from the compound (30mg, 0.082mmol) obtained in example 10-(4).
1H-NMR(400MHz,CDCl3)δ(ppm):1.22(t,J＝7.6Hz,3H),1.27(d,J＝6.6Hz,3H),2.55(s,6H),2.69(q,J＝7.6Hz,2H),3.14-3.23(m,1H),3.33-3.40(m,1H),3.64-3.71(m,1H),3.76-3.82(m,1H),3.88(s,3H),3.92-4.00(m,1H),4.19-4.25(m,1H),4.33(d,J＝14.7Hz,1H),6.92(dd,J＝1.6,7.6Hz,1H),7.06(d,J＝1.6Hz,1H),7.22(d,J＝7.6Hz,1H),7.24(s,2H)。
ESI-MS m/z 392[M+H]+
Example 11
(S)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl fluoride-5,6,8,9-tetrahydrochysene the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-6-methyl fluoride-5,6,8,9-imidazolidine also for-methyl 3-(the chloro-3-p-methoxy-phenyl of 4-) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 1-(3), title compound (1.10g, 2.98mmol) be obtained from the compound (1.39g obtained in example 1-(2), 6.18mmol) and the compound (830mg, 5.15mmol) obtained in the production instance 3-(7).
1H-NMR(400MHz,CDCl3)δ(ppm):3.04-3.14(m,1H),3.68(t,J＝11.9Hz,1H),3.76-3.86(m,1H),3.91(s,3H),3.94(s,3H),4.03(dd,J＝8.6,14.8Hz,1H),4.17(dd,J＝4.3,16.4Hz,1H),4.23-4.57(m,4H),6.94(dd,J＝1.8,8.0Hz,1H),7.14(d,J＝2.0Hz,1H),7.44(d,J＝8.2Hz,1H)。
(2) (S) the bromo-3-of-1-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl fluoride-5,6,8,9-imidazolidine also [1,5- d] synthesis of [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(4), title compound (858mg, 2.20mmol) is obtained from the compound (1.10g, 2.98mmol) obtained in example 11-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):2.94-3.06(m,1H),3.08-3.16(m,1H),3.65(ddd,J＝1.4,10.9,12.3Hz,1H),3.74-3.87(m,1H),3.94(s,3H),3.99(dd,J＝8.4,14.6Hz,1H),4.23-4.40(m,2H),4.43-4.60(m,2H),6.91(dd,J＝2.0,8.2Hz,1H),7.13(d,J＝2.0Hz,1H),7.43(d,J＝8.2Hz,1H)。
(3) (S)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl fluoride- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (364mg, 1.28mmol) be obtained from the compound (500mg obtained in example 11-(2), 1.28mmol) He 2,6-dimethyl-pyridine-4-boric acid (232mg, 1.54mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.15-3.26(m,1H),3.38(d,J＝3.9Hz,1H),3.69(t,J＝11.7Hz,1H),3.89(d,J＝7.0Hz,1H),3.95(s,3H),4.03(d,J＝15.2Hz,1H),4.27-4.42(m,2H),4.47-4.65(m,2H),6.99(dd,J＝1.8,8.0Hz,1H),7.16(d,J＝2.0Hz,1H),7.21(s,2H),7.46(d,J＝7.8Hz,1H)。
ESI-MS m/z 416[M+H]+
Example 12
(R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2-(methyl fluoride) pyridin-4-yl)-6-methyl-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-(4-(3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-base) pyridine-2-base) synthesis of methyl alcohol
According to the method for example 1-(5), title compound (53.0mg, 0.133mmol) be obtained from the compound (100mg obtained in example 1-(4), 0.269mmol) with 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) pyridine-2-base) methyl alcohol (CAS numbering 1314135-84-6; 76.0mg, 0.323mmol).
ESI-MS m/z 400[M+H]+
(2) (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2-(methyl fluoride) pyridin-4-yl)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Under ice-cooling, in the solution of the compound (50.0mg, 125 μm of ol) obtained in the example 12-(1) in DCM (2mL), BAST (32.0 μ L, 175 μm of ol) is added.This reaction mixture is heated to room temperature and stirs 13 hours further.Saturated water-based sodium hydrogen carbonate solution and DCM is added, to be separated this organic layer in this reaction mixture.By this organic over anhydrous dried over mgso, and under reduced pressure this solvent is evaporated.The resistates of this generation is carried out purifying, to obtain title compound (9.5mg, 24mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.2Hz,3H),3.17-3.26(m,1H),3.34-3.41(m,1H),3.63-3.71(m,1H),3.75-3.83(m,1H),3.95-4.03(m,1H),3.97(s,3H),4.20-4.30(m,2H),5.52(d,J＝46.9Hz,2H),6.94(dd,J＝2.0,8.0Hz,1H),7.19(d,J＝2.0Hz,1H),7.45-7.52(m,2H),7.70(s,1H),8.58(d,J＝5.2Hz,1H)。
ESI-MS m/z 402[M+H]+
Example 13
(R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2-(methyl fluoride)-6-picoline-4-base)-6-methyl-5,6,8,9- the synthesis of imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-1-(2-(((tert-butyl dimetylsilyl) oxygen base) methyl)-6-picoline-4- base) conjunction of-3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene become
According to the method for example 1-(5), title compound (283mg, 0.536mmol) be obtained from the compound (300mg obtained in example 1-(4), the compound (440mg, 1.21mmol) obtained 0.807mmol) and in production instance 24.
1H-NMR(400MHz,CDCl3)δ(ppm):0.10-0.16(m,6H),0.92-1.02(m,9H),1.26(d,J＝6.6Hz,3H),2.54(s,3H),3.10-3.24(m,1H),3.42(dd,J＝4.7,16.4Hz,1H),3.61-3.72(m,1H),3.74-3.84(m,1H),3.92-4.04(m,1H),3.96(s,3H),4.15-4.30(m,2H),4.83(s,2H),6.91-6.97(m,1H),7.20(d,J＝1.6Hz,1H),7.41-7.50(m,3H)。
(2) (R)-(4-(3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-base)-6-picoline-2-base) synthesis of methyl alcohol
At room temperature, in the solution of the compound (360mg, 0.682mmol) obtained in the example 13-(1) in THF (5.00mL), TBAF (1M THF solution, 0.818mL, 0.818mmol) is slowly added.This reaction mixture is at room temperature stirred 1 hour and adds aqueous ammonium chloride solution.Ethyl acetate is added, to be separated this organic layer in this mixture.By this organic layer continuously with water and with saturated water-based sodium chloride solution washing, with anhydrous magnesium sulfate drying, and then under reduced pressure concentrate.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) is used to carry out purifying, to obtain title compound (228mg, 0.551mmol) resistates of this generation.
1H-NMR(400MHz,CDCl3)δ(ppm):1.26(d,J＝6.3Hz,3H),2.58(s,3H),3.19(ddd,J＝2.3,10.6,16.3Hz,1H),3.30-3.40(m,1H),3.60-3.71(m,1H),3.73-3.82(m,1H),3.88(s,3H),3.88-4.03(m,1H),4.15-4.30(m,2H),4.74(s,2H),6.92(dd,J＝1.8,8.0Hz,1H),7.17(d,J＝1.6Hz,1H),7.26(s,1H),7.33(s,1H),7.46(d,J＝8.2Hz,1H)。
ESI-MS m/z 414[M+H]+
(3) (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2-(methyl fluoride)-6-picoline-4-base)-6-first base-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
At room temperature, in the solution of the compound (31mg, 75 μm of ol) obtained in the example 13-(2) in DCM (2mL), BAST (97.0 μ L, 0.524mmol) is added.This reaction mixture is stirred 13 hours, and add saturated water-based sodium hydrogen carbonate solution and DCM in this reaction mixture.This organic layer is separated and uses anhydrous magnesium sulfate drying.This organic layer is under reduced pressure concentrated.Silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) and NH silica gel column chromatography (normal heptane/ethyl acetate) is used to carry out purifying the resistates of this generation, to obtain title compound (3.5mg, 8.4 μm of ol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.2Hz,3H),2.58(s,3H),3.16-3.25(m,1H),3.34-3.41(m,1H),3.63-3.71(m,1H),3.75-3.83(m,1H),3.95-4.02(m,1H),3.97(s,3H),4.20-4.29(m,2H),5.50(d,J＝47.1Hz,2H),6.94(dd,J＝1.8,7.9Hz,1H),7.19(d,J＝1.8Hz,1H),7.42-7.48(m,3H)。
ESI-MS m/z 416[M+H]+
Example 13-A (alternative method of example 13)
(R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2-(methyl fluoride)-6-picoline-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] synthesis (example 13) of [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-(4-(3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-base) synthesis of-2,6-lutidine 1-oxide compounds
To the compound (50.0mg obtained in example 1-(5), mCPBA (by weight 75% is added in solution 0.126mmol) in DCM (2mL), 24.0mg, 0.138mmol), and this mixture is at room temperature stirred 15 hours.NH silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) is used to carry out purifying, to obtain title compound (45.0mg, 0.109mmol) in this mixture.
ESI-MS m/z 414[M+H]+
(2) (R)-(4-(3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-base)-6-picoline-2-base) synthesis of methyl alcohol
The solution of the compound (45.0mg, 109 μm of ol) that will obtain in example 13-(1)-A-(1) in diacetyl oxide (2mL) stirs 3 hours at 100 DEG C.This reaction mixture is cooled to room temperature and under reduced pressure concentrates.Chloroform and saturated water-based sodium hydrogen carbonate solution is added, to be separated this organic layer in the resistates of this generation.By this organic over anhydrous dried over mgso, and under reduced pressure this solvent is evaporated.The resistates of generation to be dissolved in methyl alcohol (3mL) and to add salt of wormwood (45.1mg, 326 μm of ol).This reaction mixture is stirred 3 hours at 80 DEG C and is then cooled to room temperature.Ethyl acetate and saturated water-based sodium hydrogen carbonate solution is added, to be separated this organic layer in this reaction mixture.By this organic over anhydrous dried over mgso, and under reduced pressure this solvent is evaporated.NH silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) and NH silica gel column chromatography (normal heptane/ethyl acetate) is used by the resistates of this generation to carry out purifying continuously, to obtain title compound (3.5mg, 8.4 μm of ol).
ESI-MS m/z 414[M+H]+
(3) (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2-(methyl fluoride)-6-picoline-4-base)-6-first base-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
At room temperature, in the solution of the compound (31mg, 75 μm of ol) obtained in the example 13-A-(2) in DCM (2mL), BAST (97.0 μ L, 0.524mmol) is added.This reaction mixture is stirred 13 hours, and then in this reaction mixture, adds saturated water-based sodium hydrogen carbonate solution and DCM.This organic layer is separated and uses anhydrous magnesium sulfate drying.This organic layer is under reduced pressure concentrated.NH silica gel column chromatography (normal heptane/ethyl acetate) and silica gel column chromatography (normal heptane/ethyl acetate) is used by the resistates of this generation to carry out purifying continuously, to obtain title compound (3.5mg, 8.4 μm of ol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.2Hz,3H),2.58(s,3H),3.16-3.25(m,1H),3.34-3.41(m,1H),3.63-3.71(m,1H),3.75-3.83(m,1H),3.95-4.02(m,1H),3.97(s,3H),4.20-4.29(m,2H),5.50(d,J＝47.1Hz,2H),6.94(dd,J＝1.8,7.9Hz,1H),7.19(d,J＝1.8Hz,1H),7.42-7.48(m,3H)。
ESI-MS m/z 416[M+H]+
Example 14
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-methyl 3-(4-(difluoro-methoxy)-3-p-methoxy-phenyl)-6-methyl-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
Compound (300mg, 1.23mmol), 4-difluoro-methoxy-3-methyl-phenylo boric acid (CAS numbering 958451-72-4 that will obtain in production instance 8-(3); 297mg, 1.47mmol), tetrakis triphenylphosphine palladium (0) (142mg, 0.123mmol), water-based sodium carbonate solution (1M, 2.45mL, 2.45mmol) and the mixture of DME (6mL) stir 30 minutes at 130 DEG C under microwave radiation.This reaction mixture is cooled to room temperature and adds ethyl acetate and saturated aqueous ammonium chloride solution.This organic layer is separated, uses saturated water-based sodium chloride solution to carry out washing and using anhydrous magnesium sulfate drying.By insolubles by filtering separation, and this filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (290mg, 0.792mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
ESI-MS m/z 367[M+H]+
(2) (R) the bromo-3-of-1-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
2N aqueous sodium hydroxide solution (0.317mL) is added in the solution of the compound (290mg, 0.792mmol) obtained in the example 14-(1) in ethanol (4mL).This reaction mixture is heated 2 hours under reflux.This reaction mixture is cooled to room temperature and uses 5N hydrochloric acid to carry out acidifying.This mixture is under reduced pressure concentrated, and adds DMF (4mL) to this resistates.In this reaction mixture, add salt of wormwood (273mg, 1.98mmol) and NBS (211mg, 1.19mmol), and this mixture is at room temperature stirred 14 hours.Water and ethyl acetate is added, to be separated this organic layer in this mixture.Saturated water-based sodium chloride solution is used by the organic layer of this generation to carry out washing and using anhydrous magnesium sulfate drying.By insolubles by filtering separation, and this filtrate is concentrated.This resistates is carried out purifying, to obtain title compound (135mg, 0.349mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.22(d,J＝6.5Hz,3H),2.32(s,3H),2.97-3.10(m,2H),3.57-3.74(m,2H),3.92(dd,J＝8.4,14.7Hz,1H),4.14-4.23(m,2H),6.55(t,J＝73.4Hz,1H),7.14(d,J＝8.4Hz,1H),7.23(dd,J＝2.3,8.4Hz,1H),7.40(d,J＝2.0Hz,1H)。
ESI-MS m/z 387[M+H]+
(3) (R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-first base-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 135mg that will obtain in example 14-(2), 0.349mmol), 2,6-dimethyl-pyridine-4-boric acid (73.7mg, 0.488mmol), tetrakis triphenylphosphine palladium (0) (20.1mg, 0.017mmol), water-based sodium carbonate solution (1M, 0.697mL), and the mixture of DME (3.00mL) under microwave radiation 150 DEG C stir 1 hour.This reaction mixture is cooled to room temperature and then uses silica gel column chromatography (normal heptane/ethyl acetate → ethyl acetate/methanol) and NH silica gel column chromatography (normal heptane/ethyl acetate) to carry out purifying continuously, to obtain title compound (104mg, 0.252mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.26(d,J＝6.7Hz,3H),2.35(s,3H),2.55(s,6H),3.14-3.22(m,1H),3.32-3.39(m,1H),3.63-3.70(m,1H),3.74-3.82(m,1H),3.94-4.01(m,1H),4.19-4.26(m,2H),6.55(t,J＝73.5Hz,1H),7.18(d,J＝8.4Hz,1H),7.21(s,2H),7.28(dd,J＝2.3,8.4Hz,1H),7.46(d,J＝1.9Hz,1H)。
ESI-MS m/z 414[M+H]+
Example 15
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 8, title compound (8.1mg, 0.020mmol) is obtained from the compound (24mg, 0.062mmol) obtained in example 14-(2).
1H-NMR(400MHz,CDCl3)δ(ppm):1.26(d,J＝6.2Hz,3H),2.35(s,3H),2.58(s,3H),3.19(ddd,J＝2.3,10.5,16.0Hz,1H),3.36(dd,J＝3.9,16.0Hz,1H),3.62-3.71(m,1H),3.74-3.84(m,1H),3.98(dd,J＝8.4,14,6Hz,1H),4.22(ddd,J＝2.3,5.1,12.1Hz,1H),4.24(d,J＝14.4Hz,1H)6.56(t,J＝73.8Hz,1H),7.15-7.22(m,1H),7.26-7.32(m,2H),7.44-7.48(m,2H),8.47-8.50(m,1H)。
ESI-MS m/z 400[M+H]+
Example 16
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-methyl 6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 14-(1), thick title compound (319mg) is obtained from the compound (200mg obtained in production instance 9, the compound (484mg, 1.52mmol) obtained 0.761mmol) and in production instance 21.
ESI-MS m/z 419[M+H]+.
(2) (S) the bromo-6-of-1-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(4), title compound (138mg, 0.314mmol) is obtained from the compound (319mg) obtained in example 16-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):2.98-3.17(m,2H),3.62-3.70(m,1H),3.78-3.88(m,1H),3.92(s,3H),3.98-4.06(m,1H),4.24-4.63(m,4H),6.96(dd,J＝2.0,8.2Hz,1H),7.20(d,J＝2.0Hz,1H),7.28-7.33(m,1H)。
(3) (S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoro methoxy base) phenyl) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (42mg, 0.09mmol) be obtained from the compound (69.0mg obtained in example 16-(2), 0.157mmol) He 2,6-dimethyl-pyridine-4-boric acid (35.6mg, 0.236mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.24(dd,J＝2.3,10.9Hz,1H),3.42(dd,J＝3.9,16.4Hz,1H),3.71(t,J＝11.5Hz,1H),3.84-3.97(m,1H),3.93(s,3H),4.06(dd,J＝8.6,14.8Hz,1H),4.28-4.66(m,4H),7.04(dd,J＝2.0,8.2Hz,1H),7.22(s,2H),7.24(d,J＝2.0Hz,1H),7.34(m,1H)。
ESI-MS m/z 466[M+H]+
Example 17
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (36mg, 0.08mmol) be obtained from the compound (69mg, 0.157mmol) obtained in example 16-(2) and 2-picoline-4-boric acid (32mg, 0.24mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.59(s,3H),3.23(ddd,J＝2.5,11.1,16.4Hz,1H),3.37-3.46(m,1H),3.72(t,J＝11.3Hz,1H),3.85-3.95(m,1H),3.94(s,3H),4.07(dd,J＝9.0,14.8Hz,1H),4.29-4.66(m,4H),7.04(dd,J＝2.0,8.2Hz,1H),7.24(d,J＝2.0Hz,1H),7.29(dd,J＝1.2,5.1Hz,1H),7.34(dq,J＝1.3,8.4Hz,1H),7.45-7.48(m,1H),8.51(d,J＝4.7Hz,1H)。
Example 18
(R)-1-(2,6-lutidine-4-base)-3-(4-methoxyl group-3-aminomethyl phenyl)-6-methyl-5,6,8,9 ,-four the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-6-methyl-5,6,8,9-imidazolidine also for-methyl 3-(4-methoxyl group-3-aminomethyl phenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 14-(1), title compound (143mg, 0.433mmol) be obtained from the compound (150mg, 0.613mmol) obtained in production instance 8-(3) and 4-methoxyl group-3-methylphenylboronic acid (CAS numbering 175883-62-2; 122mg, 0.736mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.16-1.24(m,3H),2.24(s,3H),3.01-3.17(m,1H),3.56-3.76(m,2H),3.87(s,3H),3.89(s,3H),3.90-3.98(m,1H),4.00-4.09(m,1H),4.16-4.28(m,2H),6.87(d,J＝8.4Hz,1H),7.24(dd,J＝2.2,8.4Hz,1H),7.31(d,J＝2.2Hz,1H)。
(2) (R)-6-methyl-5,6,8,9-imidazolidine also for the bromo-3-of-1-(4-methoxyl group-3-aminomethyl phenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
To the compound (143mg obtained in example 18-(1), 5N aqueous sodium hydroxide solution (433 μ L are added in solution 0.433mmol) in methyl alcohol (2.0mL)/THF (2.0mL), 2.16mL), and this mixture is at room temperature stirred 15 hours.5N hydrochloric acid is added for neutralization and by this solvent vapourisation under reduced pressure in this reaction mixture.In this resistates, add DMF (2.0mL) and ethanol (2.0mL), and add salt of wormwood (59.8mg, 0.433mL) and NBS (108mg, 0.606mmol) in this mixture.This reaction mixture is at room temperature stirred 1.5 hours, then in this reaction mixture, adds S-WAT (510mg, 4.04mL) and water.By this aqueous layer with ethyl acetate extracting twice.Saturated water-based sodium chloride solution is used by the organic layer of merging to wash twice and use anhydrous magnesium sulfate drying.This resistates is carried out purifying, to obtain title compound (81.0mg, 0.231mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate) by this solvent vapourisation under reduced pressure.
1H-NMR(400MHz,CDCl3)δ(ppm):1.15-1.24(m,3H),2.24(s,3H),2.91-3.11(m,2H),3.55-3.75(m,2H),3.87(s,3H),3.83-3.96(m,1H),4.12-4.30(m,2H),6.87(d,J＝8.4Hz,1H),7.22(dd,J＝22,8.4Hz,1H),7.28(d,J＝2.2Hz,1H)。
(3) (R)-1-(2,6-lutidine-4-base)-3-(4-methoxyl group-3-aminomethyl phenyl)-6-methyl- 5,6,8,9, the synthesis of-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 14-(3), title compound (9.1mg, 0.024mmol) be obtained from the compound (30.0mg obtained in example 18-(2), 0.085mmol) He 2,6-dimethyl-pyridine-4-boric acid (20.6mg, 0.137mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.18-1.32(m,3H),2.26(s,3H),2.55(s,6H),3.09-3.24(m,1H),3.30-3.41(m,1H),3.60-3.71(m,1H),3.73-3.83(m,1H),3.89(s,3H),3.90-4.00(m,1H),4.15-4.32(m,2H),6.90(d,J＝8.4Hz,1H),7.22(s,2H),7.27(dd,J＝2.1,8.4Hz,1H),7.33(d,J＝2.1Hz,1H)。
ESI-MS m/z 378[M+H]+
Example 19
(R)-3-(3-chloro-4-ring propoxyphenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-tetrahydrochysene the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-6-methyl-5,6,8,9-imidazolidine also for-methyl 3-(3-chloro-4-ring propoxyphenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 14-(1), title compound (89.0mg, 0.236mmol) be obtained from the compound (115mg obtained in production instance 8-(3), the compound (115mg, 0.541mmol) obtained 0.470mmol) and in production instance 12.
1H-NMR(400MHz,CDCl3)δ(ppm):0.84-0.93(m,4H),1.21-1.26(m,3H),3.00-3.21(m,1H),3.56-3.76(m,2H),3.81-3.88(m,1H),3.90(s,3H),3.93-4.10(m,2H),4.16-4.24(m,2H),7.34(dd,J＝1.8,8.6Hz,1H),7.36(dd,J＝0.6,8.6Hz,1H),7.51(dd,J＝0.6,1.8Hz,1H)。
(2) (R)-6-methyl-5,6,8,9-imidazolidine also for the bromo-3-of-1-(3-chloro-4-ring propoxyphenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 18-(2), title compound (48.0mg, 0.121mmol) is obtained from the compound (89.0mg, 0.236mmol) obtained in example 19-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):0.84-0.91(m,4H),1.21-1.26(m,3H),2.88-3.15(m,2H),3.55-3.76(m,2H),3.80-3.88(m,1H),3.89-3.98(m,1H),4.13-4.25(m,2H),7.32(dd,J＝2.0,8.5Hz,1H),7.36(d,J＝8.5Hz,1H),7.48(d,J＝2.0Hz,1H)。
(3) (R)-3-(3-chloro-4-ring propoxyphenyl)-1-(2,6-lutidine-4-base)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (15mg, 0.035mmol) be obtained from the compound (25.0mg obtained in example 19-(2), 0.063mmol) He 2,6-dimethyl-pyridine-4-boric acid (15.2mg, 0.101mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.85-0.93(m,4H),1.24-1.32(m,3H),2.55(s,6H),3.11-3.24(m,1H),3.28-3.42(m,1H),3.59-3.71(m,1H),3.72-3.90(m,2H),3.92-4.05(m,1H),4.16-4.30(m,2H),7.21(s,2H),7.37-7.40(m,2H),7.52-7.55(m,1H)。
ESI-MS m/z 424[M+H]+
Example 20
(R)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-6-methyl-5,6,8,9-imidazolidine also for-methyl 3-(4-ring propoxy--3-aminomethyl phenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 14-(1), title compound (248mg, 0.696mmol) be obtained from the compound (200mg obtained in production instance 8-(3), the compound (269mg, 0.981mmol) obtained 0.817mmol) and in production instance 16.
1H-NMR(400MHz,CDCl3)δ(ppm):0.69-0.92(m,4H),1.12-1.33(m,3H),2.19(s,3H),3.00-3.18(m,1H),3.58-3.80(m,3H),3.89(s,3H),3.90-3.98(m,1H),4.00-4.09(m,1H),4.15-4.31(m,2H),7.22-7.25(m,2H),7.28-7.30(m,1H)。
(2) (R)-6-methyl-5,6,8,9-imidazolidine also for the bromo-3-of-1-(4-ring propoxy--3-aminomethyl phenyl) the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 18-(2), title compound (115mg, 0.305mmol) is obtained from the compound (248mg, 0.696mmol) obtained in example 20-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):0.73-0.90(m,4H),1.17-1.27(m,3H),2.19(s,3H),2.90-3.01(m,1H),3.02-3.11(m,1H),3.57-3.65(m,1H),3.66-3.81(m,2H),3.84-3.96(m,1H),4.12-4.21(m,1H),4.22-4.32(m,1H),7.17-7.31(m,3H)。
(3) (R)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (2.7mg, 6.7 μm of ol) be obtained from the compound (30.0mg obtained in example 20-(2), 0.080mmol) He 2,6-dimethyl-pyridine-4-boric acid (19.2mg, 0.127mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.73-0.90(m,4H),1.21-1.32(m,3H),2.21(s,3H),2.55(s,6H),3.11-3.24(m,1H),3.28-3.43(m,1H),3.60-3.72(m,1H),3.73-3.86(m,2H),3.88-4.03(m,1H),4.16-4.35(m,2H),7.22(s,2H),7.25-7.28(m,2H),7.29-7.32(m,1H)。
ESI-MS m/z 404[M+H]+
Example 21
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-tetrahydrochysenes the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-methyl 3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine also the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 14-(1), title compound (177mg, 0.458mmol) be obtained from the compound (150mg obtained in production instance 8-(3), 0.613mmol) with 2-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes (CAS numbering 1310949-92-8; 224mg, 0.736mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.16-1.30(m,3H),3.01-3.22(m,1H),3.59-3.77(m,2H),3.90(s,3H),3.95-4.11(m,2H),4.14-4.28(m,2H),6.60(t,J＝72.8Hz,1H),7.33(d,J＝8.4Hz,1H),7.37(dd,J＝2.0,8.4Hz,1H),7.66(d,J＝2.0Hz,1H)。
(2) (R) the bromo-3-of-1-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine also the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 18-(2), title compound (98.0mg, 0.240mmol) is obtained from the compound (177mg, 0.458mmol) obtained in example 21-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):1.13-1.34(m,3H),2.91-3.03(m,1H),3.04-3.16(m,1H),3.56-3.79(m,2H),3.89-4.03(m,1H),4.14-4.25(m,2H),6.59(t,J＝72.8Hz,1H),7.32(d,J＝8.4Hz,1H),7.35(dd,J＝1.9,8.4Hz,1H),7.62(d,J＝1.9Hz,1H)。
(3) (R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 17, title compound (13.8mg, 0.033mmol) be obtained from the compound (30.0mg, 0.074mmol) obtained in example 21-(2) and 2-picoline-4-boric acid (15.1mg, 0.110mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.22-1.38(m,3H),2.59(s,3H),3.12-3.29(m,1H),3.31-3.43(m,1H),3.61-3.72(m,1H),3.74-3.87(m,1H),3.96-4.08(m,1H),4.16-4.28(m,2H),6.60(t,J＝72.9Hz,1H),7.28(brd,J＝5.2Hz,1H),7.36(brd,J＝8.4Hz,1H),7.41(dd,J＝2.0,8.4Hz,1H),7.44(brs,1H),7.68(d,J＝2.0Hz,1H),8.50(d,J＝5.2Hz,1H)。
ESI-MS m/z 420[M+H]+
Example 22
(S)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-methyl 3-(4-ring propoxy--3-aminomethyl phenyl)-6-(methyl fluoride)-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 14-(1), title compound (107mg, 0.286mmol) be obtained from the compound (200mg, 0.761mmol) obtained in production instance 9 and the compound (251mg, 0.914mmol) obtained in production instance 16.
1H-NMR(400MHz,CDCl3)δ(ppm):0.73-0.87(m,4H),2.18(s,3H),2.97-3.19(m,1H),3.63-3.72(m,1H),3.73-3.85(m,2H),3.90(s,3H),3.96-4.06(m,1H),4.12-4.20(m,1H),4.24-4.64(m,4H),7.22-7.27(m,2H),7.29-7.32(m,1H)。
(2) (S) the bromo-3-of-1-(4-ring propoxy--3-aminomethyl phenyl)-6-(methyl fluoride)-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 18-(2), title compound (75.0mg, 0.190mmol) is obtained from the compound (107mg, 0.286mmol) obtained in example 22-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):0.72-0.87(m,4H),2.18(d,J＝0.8Hz,3H),2.94-3.18(m,2H),3.57-3.70(m,1H),3.71-3.88(m,2H),3.91-4.05(m,1H),4.20-4.63(m,4H),7.24(d,J＝1.4Hz,2H),7.28(qd,J＝0.8,1.4Hz,1H)。
(3) (S)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(fluorine first base) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 14-(3), title compound (12.0mg, 0.028mmol) be obtained from the compound (26mg obtained in example 22-(2), 0.066mmol) with 2.6-lutidine-4-boric acid (15.9mg, 0.105mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):0.70-0.93(m,4H),2.20(s,3H),2.55(s,6H),3.12-3.29(m,1H),3.33-3.45(m,1H),3.64-3.74(m,1H),3.75-3.94(m,2H),3.97-4.09(m,1H),4.23-4.66(m,4H),7.22(s,2H),7.25-7.35(m,3H)。
ESI-MS m/z 422[M+H]+
Example 23
(R)-3-(4-(1,1-bis-fluoro ethyl)-3-p-methoxy-phenyl)-1-(2,6-lutidine-4-base)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R) ((1-bromo-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-also for 4-for-1- base)-2-p-methoxy-phenyl) synthesis of ethyl ketone
According to the method for production instance 14-(1) and 18-(2), title compound (79.4mg, 0.209mmol) be obtained from 1-(2-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base) phenyl) ethyl ketone (CAS numbering 638214-65-0; 293mg, 1.06mmol) and at the middle compound (173mg, 0.707mmol) obtained of production instance 8-(3).
1H-NMR(400MHz,CDCl3)δ(ppm):1.23(d,J＝6.2Hz,3H),2.64(s,3H),2.99(ddd,J＝2.7,10.9,16.4Hz,1H),3.09(ddd,J＝1.6,4.3,16.4Hz,1H),3.62(ddd,J＝1.4,10.6,12.2Hz,1H),3.67-3.76(m,1H),3.95(dd,J＝8.2,14.8Hz,1H),3.97(s,3H),4.19(ddd,J＝2.7,3.9,12.5Hz,1H),4.28(d,J＝14.4Hz,1H),6.93(dd,J＝1.6,7.8Hz,1H),7.24(d,J＝1.2Hz,1H),7.79(d,J＝7.8Hz,1H)。
ESI-MS m/z 379,381[M+H]+401,403[M+Na]+
(2) (R)-1-(4-(1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5- d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base)-2-p-methoxy-phenyl) synthesis of ethyl ketone
According to example 1-(5), title compound (35mg, 0.086mmol) is obtained from the compound (39mg, 0.10mmol) obtained in example 23-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):1.27(d,J＝6.6Hz,3H),2.56(s,6H),2.65(d,J＝0.8Hz,3H),3.19(ddd,J＝2.3,10.9,16.0Hz,1H),3.37(dd,J＝4.5,16.2Hz,1H),3.67(t,J＝11.5Hz,1H),3.75-3.85(m,1H),3.96-4.05(m,1H),3.99(s,3H),4.23(ddd,J＝2.3,4.3,12.5Hz,1H),4.30(d,J＝14.8Hz,1H),6.96-7.04(m,1H),7.22(s,2H),7.28(d,J＝0.8Hz,1H),7.82(d,J＝7.8Hz,1H)。
ESI-MS m/z 406[M+H]+,428[M+Na]+
(3) (R)-3-(4-(1,1-bis-fluoro ethyl)-3-p-methoxy-phenyl)-1-(2,6-lutidine-4-base)- the synthesis of 6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
At-78 DEG C, in the solution of the compound (35mg, 0.073mmol) obtained in the example 23-(2) in DCM (1.0mL), add DAST (23 μ L, 0.17mmol).This reaction mixture heated to room temperature and stirs 16 hours, and then adding DCE (1mL) and BAST (0.080mL, 0.43mmol).This reaction mixture be heated to 80 DEG C and stir 2 hours, and then adding BAST (0.20mL, 1.1mmol).This reaction mixture is stirred 5 hours at 80 DEG C, and then adds BAST (0.50mL, 2.7mmol).This reaction mixture is stirred 5 hours at 80 DEG C, is then cooled to room temperature, and then carry out purifying by NH silica gel column chromatography (normal heptane/ethyl acetate).Silicon thin layer chromatography (ethyl acetate) and NH silicon thin-layer chromatography (normal heptane/ethyl acetate) is used by the compound of this generation to carry out purifying, to obtain title compound (3.4mg, 0.0080mmol) continuously.
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.2Hz,3H),2.03(t,J＝18.7Hz,3H),2.63(s,6H),3.21(ddd,J＝2.3,10.7,16.2Hz,1H),3.38(dd,J＝3.9,16.0Hz,1H),3.68(t,J＝11.1Hz,1H),3.76-3.84(m,1H),3.95(s,3H),4.00(dd,J＝8.2,14.8Hz,1H),4.24(ddd,J＝2.3,4.7,12.1Hz,1H),4.30(d,J＝14.8Hz,1H),7.00(dd,J＝1.6,7.8Hz,1H),7.21(s,1H),7.30(s,2H),7.62(d,J＝7.8Hz,1H)。
ESI-MS m/z 428[M+H]+
Example 24
(R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9- the synthesis of imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-methyl 3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
Compound (the 600mg that will obtain in production instance 8-(3), 2.45mmol), the compound (1.56g obtained in production instance 21,4.90mmol), tetrakis triphenylphosphine palladium (0) (283mg, 0.245mmol), water-based sodium carbonate solution (2M, 4.9mL), and the mixture of DME (15mL) under microwave radiation 130 DEG C stir 30 minutes.This reaction mixture is cooled to room temperature and then adds ethyl acetate and saturated aqueous ammonium chloride solution.Insolubles is filtered out by Celite (trade mark) and is separated by the organic layer of the filtrate of this generation.The saturated water-based sodium chloride solution of the organic layer of this generation is washed, with anhydrous magnesium sulfate drying, this siccative is filtered out, and by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain title compound (982mg, 2.45mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
ESI-MS m/z 401[M+H]+
(2) (R) the bromo-3-of-1-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
5N aqueous sodium hydroxide solution (0.981mL) is added in the solution of the compound (982mg, 2.45mmol) obtained in the example 24-(1) in ethanol (10.0mL).By the heating of this reaction mixture and 45 DEG C of stirrings 4 hours.This reaction mixture is cooled to room temperature, then adds 5N hydrochloric acid (0.98mL) for neutralization.Insolubles is filtered out, then this filtrate is under reduced pressure concentrated, and then in the resistates of this generation, add DMF (5mL).In this reaction mixture, add salt of wormwood (678mg, 4.91mmol) and NBS (480mg, 2.70mmol), and this mixture is at room temperature stirred 14 hours.Water and ethyl acetate is added, to be separated this organic layer in this mixture.The saturated water-based sodium chloride solution of the organic layer of this generation is washed, with anhydrous magnesium sulfate drying, this siccative is filtered out, and then by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain title compound (640mg, 1.52mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.24(d,J＝6.3Hz,3H),2.94-3.12(m,2H),3.58-3.66(m,1H),3.67-3.76(m,1H),3.93(s,3H),3.94-3.99(m,1H),4.15-4.22(m,1H),4.23-4.30(m,1H),6.83-6.93(m,1H),7.20-7.24(m,1H),7.27-7.33(m,1H)。
(3) (R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4- base) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 640mg that will obtain in example 24-(2), 1.52mmol), 2-picoline-4-boric acid (312mg, 2.28mmol), tetrakis triphenylphosphine palladium (0) (176mg, 0.152mmol), water-based sodium carbonate solution (2M, 3.04mL, 6.08mmol), and the mixture of DME (10mL) under microwave radiation 150 DEG C stir 30 hours.This reaction mixture is cooled to room temperature and add ethyl acetate and saturated aqueous ammonium chloride solution for separating of.The saturated water-based sodium chloride solution of the organic layer of this generation is washed, then uses anhydrous magnesium sulfate drying, this siccative is filtered out, and then by this solvent vapourisation under reduced pressure.NH silica gel column chromatography (heptane-ethyl acetate) and silica gel column chromatography (methanol-ethyl acetate) is used by the resistates of this generation to carry out purifying, to obtain title compound (152mg, 0.351mmol) continuously.
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.3Hz,3H),2.59(s,3H),3.16-3.26(m,1H),3.33-3.42(m,1H),3.64-3.73(m,1H),3.76-3.85(m,1H),3.95(s,3H),3.96-4.05(m,1H),4.19-4.32(m,2H),6.95-7.00(m,1H),7.25-7.36(m,3H),7.45-7.48(m,1H),8.47-8.52(m,1H)。
ESI-MS m/z 434[M+H]+。
Example 25
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 7-(5), title compound (6.7mg, 0.015mmol) be obtained from the compound (19mg obtained in example 24-(2), 0.045mmol) He 2,6-dimethyl-pyridine-4-boric acid (14mg, 0.093mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.2Hz,3H),2.56(s,6H),3.19(ddd,J＝2.3,10.5,16.0Hz,1H),3.37(dd,J＝3.9,16.0Hz,1H),3.67(t,J＝11.3Hz,1H),3.75-3.84(m,1H),3.94(s,3H),4.00(dd,J＝8.6,14.8Hz,1H),4.23(ddd,J＝2.3,4.7,12.5Hz,1H),4.27(d,J＝14.8Hz,1H),6.97(dd,J＝2.0,8.6Hz,1H),7.22(s,2H),7.26(d,J＝2.0Hz,1H),7.33(d,J＝1.2,8.2Hz,1H)。
ESI-MS m/z 448[M+H]+。
Example 26
(S)-3-(the chloro-3-p-methoxy-phenyl of 4-)-6-methyl fluoride-1-(2-picoline-4-base)-5,6,8,9-imidazolidines and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (13.3mg, 0.033mmol) be obtained from the compound (30.0mg obtained in example 11-(2), 0.077mmol) with 2-picoline-4-boric acid (21.1mg, 0.154mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.59(s,3H),3.15-3.28(m,1H),3.41(dd,J＝4.1,16.2Hz,1H),3.70(t,J＝11.5Hz,1H),3.84-3.93(m,1H),3.95(s,3H),4.04(dd,J＝9.0,14.8Hz,1H),4.26-4.44(m,2H),4.47-4.64(m,2H),6.96-7.03(m,1H),7.16(d,J＝2.0Hz,1H),7.30(d,J＝5.1Hz,1H),7.44-7.51(m,2H),8.50(d,J＝5.5Hz,1H)。
ESI-MS m/z 402[M+H]+
Example 27
(S)-3-(4-difluoro-methoxy-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-methyl 3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-(methyl fluoride)-5,6,8,9-tetrahydrochysene the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
By the compound (203mg obtained in production instance 9 in DME (3.09mL), 0.773mmol), 4-difluoro-methoxy-3-methyl-phenylo boric acid (234mg, 1.16mmol), tetrakis triphenylphosphine palladium (0) (89mg, 0.077mmol) and the mixture of water-based sodium carbonate solution (1M, 1.47mL) under microwave radiation 130 DEG C stir 30 minutes.Ethyl acetate and watersoluble chlorinated sodium solution is added in this mixture.This organic layer is separated.This water layer is made to be extracted with ethyl acetate three times, then then the organic over anhydrous dried over sodium sulfate of this generation is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (281mg, 0.731mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
ESI-MS m/z 385[M+H]+
(2) (S) the bromo-3-of-1-(4-difluoro-methoxy-3-aminomethyl phenyl)-6-(methyl fluoride)-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 281mg that will obtain in example 27-(1), 0.731mmol) at room temperature stir 2 hours with the solution of 5N aqueous sodium hydroxide solution (0.731mL, 3.66mmol) in THF (1.8mL)-methyl alcohol (1.8mL).Hydrochloric acid is used to neutralize this reaction mixture.This mixture is under reduced pressure concentrated and the resistates of generation and toluene are carried out azeotropic.DMF (3.6mL), ethanol (3.6mL), salt of wormwood (101mg, 0.731mmol) is added to this resistates, and NBS (260mg, 1.46mmol), and this mixture is at room temperature stirred 16 hours.S-WAT is added also under reduced pressure by ethanol evaporation in this reaction mixture.In the solution of this generation, add ethyl acetate, and then this mixture made to wash five times with water and then use saturated water-based sodium chloride solution to wash.This organic over anhydrous dried over sodium sulfate is also under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (140mg, 0.346mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.33(s,3H),3.02(ddd,J＝2.7,10.9,16.4Hz,1H),3.12(ddd,J＝1.2,3.5,16.4Hz,1H),3.65(dt,J＝1.2,11.7Hz,1H),3.74-3.86(m,1H),4.00(dd,J＝8.8,14.6Hz,1H),4.23-4.30(m,1H),4.40(ddd,J＝6.6,9.4,46.9Hz,1H)4.51(ddd,J＝4.7,9.8,46.1Hz,1H),4.53(d,J＝14.8Hz,1H),6.55(t,J＝73.4Hz,1H),7.15(d,J＝8.6Hz,1H),7.27(dd,J＝2.0,8.2Hz,1H),7.41(d,J＝2.0Hz,1H)。
ESI-MS m/z 405,407[M+H]+427,429[M+Na]+
(3) (S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6- the synthesis of (methyl fluoride)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 28mg that will obtain in example 27-(2), 0.069mmol), 2,6-dimethyl-pyridine-4-boric acid (20.9mg, 0.138mmol), tetrakis triphenylphosphine palladium (0) (8.0mg, 0.0069mmol), water-based sodium carbonate solution (1M, 0.35mL), and the mixture of DME (0.70mL) under microwave radiation 150 DEG C stir 30 minutes.In this mixture, add ethyl acetate, then this mixture is filtered by silicagel pad (NH silica gel), and then this filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain this title compound (21.0mg, 0.049mmol) by silicon thin-layer chromatography (ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.35(s,3H),2.56(s,6H),3.21(ddd,J＝2.7,11.3,16.4Hz,1H),3.41(dd,J＝3.9,16.0Hz,1H),3.70(t,J＝11.3Hz,1H),3.83-3.94(m,1H),4.05(d,J＝9.0,14.8Hz,1H),4.28-4.46(m,2H),4.55(ddd,J＝5.1,9.8,46.5Hz,1H),4.55(d,J＝14.8Hz,1H),6.56(t,J＝73.4Hz,1H),7.17-7.21(m,1H),7.21(s,2H),7.33(d,J＝2.1,8.4Hz,1H),7.47(d,J＝2.0Hz,1H)。
ESI-MS m/z 432[M+H]+
Example 28
(S)-3-(4-(difluoromethyl)-3-p-methoxy-phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S) the bromo-3-of-1-(4-difluoromethyl-3-p-methoxy-phenyl)-6-(methyl fluoride)-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 27-(1) and 27-(2), title compound (107mg, 0.264mmol) be obtained from the compound (140mg obtained in production instance 9,0.533mmol) with 2-(4-(difluoromethyl)-3-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes (CAS numbering 1310949-77-9; 267mg, 0.940mmol).
ESI-MS m/z 405,407[M+H]+427,429[M+Na]+
(2) (S)-3-(4-(difluoromethyl)-3-p-methoxy-phenyl)-1-(2,6-lutidine-4-base)-6- the synthesis of (methyl fluoride)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 27-(3), title compound (16mg, 0.037mmol) is obtained from the compound (21mg, 0.052mmol) obtained in example 28-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):2.57(s,6H),3.22(ddd,J＝2.3,10.9,16.4Hz,1H),3.42(dd,J＝3.7,16.2Hz,1H),3.71(t,J＝11.3Hz,1H),3.84-3.96(m,1H),3.93(s,3H),4.06(dd,J＝8.6,14.8,1H),4.28-4.66(m,4H),6.98(t,J＝55.5Hz,1H),7.10-7.25(m,4H),7.67(d,J＝7.8Hz,1H)。
ESI-MS m/z 432[M+H]+
Example 29
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-methyl 6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-tetrahydrochysenes the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
By the compound (202mg obtained in production instance 9 in DME (3.08mL), 0.769mmol), 2-(3-methoxyl group-4-(trifluoromethyl) phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxaborolanes (CAS numbering 1004775-33-0; 465mg, 1.54mmol), the mixture of tetrakis triphenylphosphine palladium (0) (89mg, 0.077mmol) and water-based sodium carbonate solution (1M, 1.46mL) stirs 30 minutes at 130 DEG C under microwave radiation.Ethyl acetate and sodium-chlor are added in this mixture.This organic layer is separated.This water layer is made to be extracted with ethyl acetate four times, and then that the organic over anhydrous sodium sulphate of this generation is dry and then under reduced pressure concentrate.The resistates of this generation is carried out purifying, to obtain thick title compound (391mg) by silica gel column chromatography (normal heptane/ethyl acetate).
ESI-MS m/z 403[M+H]+
(2) (S) the bromo-6-of-1-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-tetrahydrochysenes the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
The compound (391mg) obtained in example 29-(1) and the solution of 5N aqueous sodium hydroxide solution (0.972mL) in THF (2.4mL)/methyl alcohol (2.4mL) are at room temperature stirred 3 hours.Hydrochloric acid is used to neutralize this reaction mixture.This mixture is under reduced pressure concentrated and by the resistates that generates and methylbenzene azeotropic.At room temperature, add DMF (2.4mL), ethanol (2.4mL), salt of wormwood (134mg, 0.972mmol) to this resistates, and NBS (346mg, 1.94mmol).At room temperature this reaction mixture is stirred 20 hours.In this reaction mixture, add NBS (346mg, 1.94mmol) and then this mixture is stirred 5 hours.S-WAT is added also under reduced pressure by ethanol evaporation in this reaction mixture.In the solution of this generation, add ethyl acetate, and this mixture is made to wash five times with water and then uses saturated water-based sodium chloride solution to wash.This organic over anhydrous dried over sodium sulfate is also under reduced pressure concentrated.The resistates of this generation is carried out purifying by silica gel column chromatography, to obtain title compound (179mg, 0.423mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):3.06(ddd,J＝2.7,10.9,16.0Hz,1H),3.14(ddd,J＝1.6,3.9,16.4Hz,1H),3.66(ddd,J＝1.4,10.9,12.3Hz,1H),3.79-3.89(m,1H),3.95(s,3H),4.02(dd,J＝8.6,14.8Hz,1H),4.25-4.42(m,2H),4.53(ddd,J＝4.7,9.4,46.1Hz,1H),4.59(d,J＝15.6Hz,1H),7.03(d,J＝7.8Hz,1H),7.22(s,1H),7.64(d,J＝7.8Hz,1H)。
ESI-MS m/z 423,425[M+H]+445,447[M+Na]+
(3) (S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 26mg that will obtain in example 29-(2), 0.061mmol), 2,6-dimethyl-pyridine-4-boric acid (18.6mg, 0.123mmol), tetrakis triphenylphosphine palladium (0) (7.1mg, 0.0061mmol), water-based sodium carbonate solution (1M, 0.40mL), and the mixture of DME (0.80mL) under microwave radiation 150 DEG C stir 30 minutes.In this mixture, add ethyl acetate, and then this mixture is filtered by a kind of silicagel pad (NH silica gel), and then under reduced pressure concentrate.The resistates of this generation is carried out purifying, to obtain this title compound (17.3mg, 0.038mmol) by silicon thin-layer chromatography (ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.57(s,6H),3.21(ddd,J＝2.7,11.3,16.4Hz,1H)3.42(dd,J＝4.1,16.2Hz,1H),3.71(t,J＝11.7Hz,1H),3.87-3.99(m,1H),3.97(s,3H),4.07(dd,J＝9.0,14.8Hz,1H),4.28-4.47(m,2H),4.57(ddd,J＝4.5,9.6,46.1Hz,1H),4.62(d,J＝14.4Hz,1H),7.10(d,J＝7.8Hz,1H),7.21(s,2H),7.26(s,1H),7.67(d,J＝7.8Hz,1H)。
ESI-MS m/z 450[M+H]+
Example 30
(R)-1-(2-(methyl fluoride)-6-picoline-4-base)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6- methyl-5,6, the synthesis of 8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-(4-(3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl-5,6,8,9-tetrahydrochysene miaow azoles is [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-base also)-6-picoline-2-base) synthesis of methyl alcohol
According to the method for example 1-(5), title compound (7.1mg, 0.015mmol) be obtained from the compound (39mg obtained in example 24-(2), the compound (37.7mg, 0.185mmol) obtained 0.093mmol) and in production instance 23.
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.6Hz,3H),2.59(s,3H),3.20(ddd,J＝2.3,10.5,16.0Hz,1H),3.37(dd,J＝4.1,16.2Hz,1H),3.67(t,J＝11.3Hz,1H),3.76-3.84(m,1H),3.95(s,3H),4.00(dd,J＝8.6,14.8Hz,1H),4.23(ddd,J＝2.3,5.1,12.5Hz,1H),4.28(d,J＝14.8Hz,1H),4.75(s,2H),6.97(dd,2.0,8.2Hz,1H),7.25(d,J＝1.6Hz,1H),7.26-7.29(m,1H),7.31-7.40(m,2H)。
ESI-MS m/z 464[M+H]+
(2) (R)-1-(2-(methyl fluoride)-6-picoline-4-base)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl) synthesis of-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
At-78 DEG C, in the solution of the compound (7.1mg, 0.015mmol) obtained in the example 30-(1) in DCM (1.0mL), add DAST (12 μ L, 0.091mmol).This reaction soln is heated to room temperature, stirs 16 hours and then filtered by a kind of silicagel pad (NH silica gel).Under reduced pressure this filtrate concentrated and then the resistates of this generation carried out purifying by silicon thin-layer chromatography (ethyl acetate), to obtain title compound (3.5mg, 0.0075mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.6Hz,3H),2.58(s,3H),3.22(ddd,J＝2.3,10.7,16.2Hz,1H),3.38(dd,J＝4.7,16.4Hz,1H),3.68(dd,J＝10.5,11.7Hz,1H),3.75-3.84(m,1H),3.95(s,3H),4.01(dd,J＝8.2,14.8Hz,1H),4.24(ddd,J＝2.3,4.7,12.1Hz,1H),4.28(d,J＝14.4Hz,1H),5.49(d,J＝46.9Hz,2H),6.98(dd,2.0,8.6Hz,1H),7.24-7.27(m,1H),7.31-7.36(m,1H),7.43(s,1H),7.46(s,1H)。
ESI-MS m/z 466[M+H]+488[M+Na]+
Example 31
(S)-1-(2-(difluoromethyl)-6-picoline-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(fluoroform base) phenyl) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-1-(2-(((tert-butyl dimethylsilane) oxygen base) methyl)-6-picoline-4-base)-6- (methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine tall and erect synthesis
According to the method for example 1-(5), thick title compound (148mg, 0.255mmol) be obtained from the compound (140mg obtained in example 29-(2), 0.331mmol) and the compound (162mg, 0.446mmol) obtained in the production instance 24-(2).
ESI-MS m/z 580[M+H]+
(2) (S)-(4-(6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-tetrahydrochysene miaows azoles is [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-base also)-6-picoline-2-base) synthesis of methyl alcohol
At room temperature, in the solution of the compound (144mg, 0.248mmol) obtained in the example 31-(1) in THF (3mL), TBAF (1M THF solution, 0.373mL, 0.373mmol) is added.This mixture is at room temperature stirred 30 minutes, then adds ethyl acetate and water, to be separated this organic layer.Saturated water-based sodium chloride solution is used by the organic layer of this generation to carry out washing and using anhydrous magnesium sulfate drying.This siccative is filtered out, and then by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain title compound (88.0mg, 0.189mmol) by NH silica gel column chromatography (ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.60(s,3H),3.17-3.29(m,1H),3.42(dd,J＝4.0,16.0Hz,1H),3.71(t,J＝12.0Hz,1H),3.84-3.95(m,2H),3.97(s,3H),4.08(dd,J＝8.0,16.0Hz,1H),4.28-4.66(m,4H),4.76(s,2H),7.10(d,J＝7.8Hz,1H),7.24(s,1H),7.27(s,1H),7.33(s,1H),7.68(d,J＝7.8Hz,1H)。
(3) (S)-1-(2-(difluoromethyl)-6-picoline-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4- (trifluoromethyl) phenyl) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
At room temperature, in the solution of the compound (60.0mg, 0.129mmol) obtained in the example 31-(2) in DCM (2.5mL), DMPI (82.0mg, 0.193mmol) is added.This reaction mixture is at room temperature stirred 1 hour and then adds saturated water-based hypo solution, saturated water-based sodium hydrogen carbonate solution and ethyl acetate, to be separated this organic layer.The saturated water-based sodium chloride solution of the organic layer of this generation is washed, with anhydrous magnesium sulfate drying, this siccative is filtered out, and then by this solvent vapourisation under reduced pressure.The resistates of this generation to be dissolved in DCM (2.5mL) and dropwise to add DAST (0.043mL, 0.32mmol) wherein at-20 DEG C.This mixture is slowly heated to room temperature, stirs 3 hours, and in this reaction mixture, add frozen water, saturated water-based sodium hydrogen carbonate solution, and ethyl acetate, to be separated this organic layer.The saturated water-based sodium chloride solution of the organic layer of this generation is washed, and then uses anhydrous magnesium sulfate drying, this siccative is filtered out, and then by this solvent vapourisation under reduced pressure.The resistates of this generation is carried out purifying, to obtain title compound (55.3mg, 0.114mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):2.63(s,3H),3.22-3.32(m,1H),3.42(dd,J＝4.0,16.0Hz,1H),3.72(t,J＝11.1Hz,1H),3.87-3.96(m,1H),3.97(s,3H),4.09(dd,J＝8.6,14.8Hz,1H),4.29-4.66(m,4H),6.64(t,J＝56.0Hz,1H),7.09-7.13(m,1H),7.25(s,1H),7.58(s,1H),7.63(s,1H),7.68(d,J＝8.2Hz,1H)。
ESI-MS m/z 486[M+H]+。
Example 32
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9- the synthesis of imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R)-methyl 3-(the chloro-4-of 3-(methoxymethoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
Compound (the 470mg that will obtain in production instance 8-(3), 1.92mmol), the compound (688mg obtained in production instance 13,2.31mmol), tetrakis triphenylphosphine palladium (0) (166mg, 0.144mmol), the mixture of water-based sodium carbonate solution (2M, 1.92mL) and DME (7.5mL) stirs 2 hours at 130 DEG C under microwave radiation.This reaction mixture is cooled to room temperature, and adds ethyl acetate and water, to be separated this organic layer.Used by this organic layer saturated water-based sodium chloride solution to wash, with anhydrous magnesium sulfate drying, and under reduced pressure concentrate.The resistates of this generation is carried out purifying, to obtain title compound (460mg, 1.21mmol) by silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.20-1.26(m,3H),3.02-3.17(m,1H),3.54(s,3H),3.59-3.77(m,2H),3.90(s,3H),3.92-4.09(m,2H),4.16-4.24(m,2H),5.31(s,2H),7.25(d,J＝8.6Hz,1H),7.30(dd,J＝2.1,8.6Hz,1H),7.57(d,J＝2.1Hz,1H)。
(2) (R) the bromo-3-of-1-(the chloro-4-of 3-(methoxymethoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine and the synthesis of [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 460mg that will obtain in example 32-(1), 1.21mmol) be dissolved in THF (5mL) and methyl alcohol (5mL), and add 5N aqueous sodium hydroxide solution (1.21mL, 6.04mmol).At room temperature this mixture is stirred 15 hours, use the neutralization of 5N hydrochloric acid, and under reduced pressure concentrate.The resistates of this generation is dissolved in ethanol (5mL) and DMF (5mL), adds salt of wormwood (167mg, 1.21mmol) and NBS (301mg, 1.69mmol), and this mixture is at room temperature stirred 2 hours.S-WAT (1.22g, 9.66mmol) is added, water in this reaction mixture, and ethyl acetate, to be separated this organic layer.Used by the organic layer of this generation saturated water-based sodium chloride solution to wash, with anhydrous magnesium sulfate drying, and under reduced pressure concentrate.This resistates is carried out purifying, to obtain title compound (240mg, 0.597mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.20-1.26(m,3H),2.91-3.01(m,1H),3.02-3.14(m,1H),3.54(s,3H),3.56-3.77(m,2H),3.84-4.01(m,1H),4.10-4.28(m,2H),5.30(s,2H),7.24(d,J＝8.6Hz,1H),7.28(dd,J＝2.0,8.6Hz,1H),7.53(d,J＝2.0Hz,1H)。
(3) (R)-3-(the chloro-4-of 3-(methoxymethoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8, the synthesis of 9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Compound (the 200mg that will obtain in example 32-(2), 0.498mmol), 2,6-lutidine-4-boric acid (120mg, 0.797mmol), tetrakis triphenylphosphine palladium (0) (43.2mg, 0.0370mmol), water-based sodium carbonate solution (2M, 0.80mL), and the mixture of DME (1.7mL) under microwave radiation 120 DEG C stir 1 hour.This reaction mixture is cooled to room temperature, and adds water and ethyl acetate, to be separated this organic layer.Used by the organic layer of this generation saturated water-based sodium chloride solution to wash, with anhydrous magnesium sulfate drying, and under reduced pressure concentrate.The resistates of this generation is carried out purifying by NH silica gel column chromatography (normal heptane/ethyl acetate).Silica gel chromatography (ethyl acetate/methanol) is used to be further purified, to obtain this title compound (175mg, 0.409mmol) on this resultant.
1H-NMR(400MHz,CDCl3)δ(ppm):1.23-1.32(m,3H),2.55(s,6H),3.10-3.25(m,1H),3.29-3.40(m,1H),3.55(s,3H),3.60-3.71(m,1H),3.73-3.85(m,1H),3.91-4.04(m,1H),4.17-4.28(m,2H),5.31(s,2H),7.20(s,2H),7.27(d,J＝8.6Hz,1H),7.33(dd,J＝2.0,8.6Hz,1H),7.59(d,J＝2.0Hz,1H)。
(4) (R) [-6-methyl-5,6,8,9-imidazolidine also for 1-(2,6-lutidine-4-base) for the chloro-4-of-2- [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base] synthesis of phenol
Compound (the 175mg that will obtain in example 32-(3), 0.409mmol) be dissolved in methyl alcohol (8mL), and at room temperature add 5N hydrochloric acid (0.818mL, 4.09mmol), and this mixture is stirred 3 hours at 70 DEG C.This reaction mixture is cooled to room temperature, and then adds saturated water-based sodium hydrogen carbonate solution, and then vapourisation under reduced pressure methyl alcohol.In this resistates, add ethyl acetate and water and the solid by filtration of this generation is collected.By the solid drying under reduced pressure of this generation, to obtain thick title compound (360mg).
1H-NMR(400MHz,CDCl3)δ(ppm):1.23-1.29(m,3H),2.55(s,6H),3.10-3.24(m,1H),3.29-3.40(m,1H),3.59-3.85(m,2H),3.90-4.04(m,1H),4.16-4.27(m,2H),7.10(d,J＝8.2Hz,1H),7.20(s,2H),7.27(dd,J＝2.0,8.2Hz,1H),7.56(d,J＝2.0Hz,1H)。
(5) (R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl the synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Crude product (69mg), the difluoro sodium chloroacetate (29.8mg of the compound that will obtain in example 32-(4), 0.195mmol), cesium carbonate (33.1mg, 0.102mmol), stir 4 hours at 80 DEG C with the mixture in DMF (0.30mL) of water (35.2 μ L, 1.95mmol).This reaction mixture is cooled to room temperature, and then adds water and ethyl acetate, to be separated this organic layer.By this organic over anhydrous dried over mgso, and under reduced pressure by this solvent concentration.NH silica gel column chromatography (normal heptane/ethyl acetate) and silicon thin-layer chromatography (ethyl acetate/methanol) is used by the resistates of this generation to carry out purifying, to obtain title compound (6.7mg, 0.015mmol) continuously.
1H-NMR(400MHz,CDCl3)δ(ppm):1.22-1.35(m,3H),2.56(s,6H),3.11-3.28(m,1H),3.29-3.43(m,1H),3.60-3.72(m,1H),3.73-3.88(m,1H),3.93-4.08(m,1H),4.14-4.29(m,2H),6.60(t,J＝73.0Hz,1H),7.19(s,2H),7.35(d,J＝8.4Hz,1H),7.40(dd,J＝2.0,8.4Hz,1H),7.68(d,J＝2.0Hz,1H)。
ESI-MS m/z 434[M+H]+
Example 33
(R)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
By cesium carbonate (34.0mg, 0.104mmol) add the compound (46mg), methyl-sulfate (the 9.86 μ L that obtain in example 32-(4) to, 0.104mmol) and in the mixture of DMF (0.3mL), and this mixture is at room temperature stirred 1 hour.This reaction mixture is diluted with DCM and the solid by filtration separation that will generate.This filtrate is under reduced pressure concentrated and the resistates of this generation is carried out purifying, to obtain title compound (8.1mg, 0.020mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.23-1.35(m,3H),2.55(s,6H),3.10-3.24(m,1H),3.28-3.42(m,1H),3.59-3.71(m,1H),3.72-3.85(m,1H),3.89-4.05(m,1H),3.97(s,3H),4.16-4.29(m,2H),7.02(d,J＝8.4Hz,1H),7.20(s,2H),7.38(dd,J＝2.1,8.4Hz,1H),7.56(d,J＝2.1Hz,1H)。
ESI-MS m/z 398[M+H]+
Example 34
(R)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-tetrahydrochysene miaow the synthesis of azoles also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 33, title compound (10.6mg, 0.026mmol) is obtained from the compound (46mg) and iodoethane (8.33 μ L, 0.104mmol) that obtain in example 32-(4).
1H-NMR(400MHz,CDCl3)δ(ppm):1.22-1.33(m,3H),1.51(t,J＝7.0Hz,3H),2.55(s,6H),3.10-3.25(m,1H),3.29-3.42(m,1H),3.59-3.72(m,1H),3.72-3.84(m,1H),3.91-4.04(m,1H),4.17(q,J＝7.0Hz,2H),4.17-4.28(m,2H),7.00(d,J＝8.5Hz,1H),7.20(s,2H),7.35(dd,J＝2.1,8.5Hz,1H),7.55(d,J＝2.1Hz,1H)。
ESI-MS m/z 412[M+H]+
Example 35
(R)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-tetrahydrochysene the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
To the compound (46mg), 2-N-PROPYLE BROMIDE (the 9.78 μ L that obtain in example 32-(4), 0.104mmol), cesium carbonate (50.9mg, 0.156mmol) is added with in the mixture of DMF (0.3mL).This reaction mixture is stirred 2 hours at 100 DEG C.This reaction mixture is cooled to room temperature and then uses DCM dilution.The insolubles produced is passed through filtering separation, and this filtrate is under reduced pressure concentrated.The resistates of this generation is carried out purifying, to obtain title compound (12.0mg, 0.028mmol) by NH silica gel column chromatography (normal heptane/ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.24-1.30(m,3H),1.42(d,J＝6.1Hz,6H),2.55(s,6H),3.09-3.25(m,1H),3.29-3.42(m,1H),3.59-3.71(m,1H),3.72-3.86(m,1H),3.88-4.04(m,1H),4.15-4.29(m,2H),4.63(sep,J＝6.1Hz,1H),7.03(d,J＝8.5Hz,1H),7.21(s,2H),7.35(dd,J＝2.1,8.5Hz,1H),7.53(d,J＝2.1Hz,1H)。
ESI-MS m/z 426[M+H]+
Example 36
(S)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (S)-methyl 3-(the chloro-4-of 3-(methoxymethoxy) phenyl)-6-(methyl fluoride)-5,6,8,9-tetrahydrochysene the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-1-carboxylicesters
According to the method for example 32-(1), title compound (760mg, 1.91mmol) be obtained from the compound (600mg, 2.28mmol) obtained in production instance 9 and the compound (818mg, 2.74mmol) obtained in production instance 13.
1H-NMR(400MHz,CDCl3)δ(ppm):3.00-3.17(m,1H),3.54(s,3H),3.62-3.72(m,1H),3.73-3.86(m,1H),3.91(s,3H),3.99-4.10(m,1H),4.12-4.21(m,1H),4.23-4.66(m,4H),5.30(s,2H),7.25(d,J＝8.6Hz,1H),7.31(dd,J＝2.1,8.6Hz,1H),7.60(d,J＝2.1Hz,1H)。
(2) (S) the bromo-3-of-1-(the chloro-4-of 3-(methoxymethoxy) phenyl)-6-(methyl fluoride)-5,6,8,9-tetrahydrochysene the synthesis of imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 32-(2), title compound (530mg, 1.26mmol) is obtained from the compound (760mg, 1.91mmol) obtained in example 36-(1).
1H-NMR(400MHz,CDCl3)δ(ppm):2.85-3.18(m,2H),3.54(s,3H),3.59-3.70(m,1H),3.73-3.87(m,1H),3.95-4.09(m,1H),4.19-4.63(m,4H),5.30(s,2H),7.25(d,J＝8.6Hz,1H),7.29(dd,J＝2.1,8.6Hz,1H),7.56(d,J＝2.1Hz,1H)。
(3) (S)-3-(the chloro-4-of 3-(methoxymethoxy) phenyl)-1-(2,6-lutidine-4-base)-6- the synthesis of (methyl fluoride)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 32-(3), title compound (154mg, 0.345mmol) be obtained from the compound (200mg obtained in example 36-(2), 0.477mmol) He 2,6-lutidine-4-boric acid (115mg, 0.762mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.11-3.30(m,1H),3.33-3.48(m,1H),3.55(s,3H),3.62-3.77(m,1H),3.79-3.95(m,1H),3.99-4.11(m,1H),4.24-4.69(m,4H),5.31(s,2H),7.20(s,2H),7.28(d,J＝8.6Hz,1H),7.35(dd,J＝2.2,8.6Hz,1H),7.61(d,J＝2.2Hz,1H)。
(4) (S) the chloro-4-of-2-(1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine and [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base) synthesis of phenol
According to the method for example 32-(4), thick title compound (330mg) is obtained from the compound (154mg, 0.345mmol) obtained in example 36-(3).
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.14-3.28(m,1H),3.34-3.47(m,1H),3.62-3.76(m,1H),3.78-3.94(m,1H),3.98-4.09(m,1H),4.24-4.67(m,4H),7.10(d,J＝8.4Hz,1H),7.20(s,2H),7.30(dd,J＝2.1,8.4Hz,1H),7.58(d,J＝2.1Hz,1H)。
(5) (S)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 33, title compound (5.1mg, 0.012mmol) is obtained from the compound (48mg) and methyl-sulfate (9.42 μ L, 0.100mmol) that obtain in example 36-(4).
1H-NMR(400MHz,CDCl3)δ(ppm):2.56(s,6H),3.14-3.29(m,1H),3.33-3.44(m,1H),3.62-3.76(m,1H),3.79-3.92(m,1H),3.97(s,3H),4.00-4.10(m,1H),4.25-4.67(m,4H),7.03(d,J＝8.6Hz,1H),7.20(s,2H),7.39(dd,J＝2.1,8.6Hz,1H),7.60(d,J＝2.1Hz,1H)。
ESI-MS m/z 416[M+H]+
Example 37
(S)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-tetra- the synthesis of hydrogen imidazo [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 33, title compound (8.8mg, 0.020mmol) is obtained from the compound (48mg) and iodoethane (7.96 μ L, 0.100mmol) that obtain in example 36-(4).
1H-NMR(400MHz,CDCl3)δ(ppm):1.51(t,J＝7.0Hz,3H),2.56(s,6H),3.11-3.29(m,1H),3.33-3.46(m,1H),3.60-3.77(m,1H),3.79-3.94(m,1H),3.98-4.10(m,1H),4.17(q,J＝7.0Hz,2H),4.24-4.66(m,4H),7.01(d,J＝8.6Hz,1H),7.20(s,2H),7.36(dd,J＝2.1,8.6Hz,1H),7.59(d,J＝2.1Hz,1H)。
ESI-MS m/z 430[M+H]+
Example 38
(S)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9- the synthesis of imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 35, title compound (14.0mg, 0.032mmol) is obtained from the compound (48mg) and 2-N-PROPYLE BROMIDE (9.35 μ L, 0.100mmol) that obtain in example 36-(4).
1H-NMR(400MHz,CDCl3)δ(ppm):1.42(d,J＝6.1Hz,6H),2.56(s,6H),3.11-3.29(m,1H),3.33-3.48(m,1H),3.63-3.75(m,1H),3.78-3.95(m,1H),3.98-4.11(m,1H),4.24-4.63(m,4H),4.64(sep,J＝6.1Hz,1H),7.03(d,J＝8.6Hz,1H),7.20(s,2H),7.36(dd,J＝2.2,8.6Hz,1H),7.57(d,J＝2.2Hz,1H)。
ESI-MS m/z 444[M+H]+
Example 39
(R)-3-(3-(methyl fluoride)-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
(1) (R) the bromo-3-of-1-(3-((methoxymethoxy) methyl)-4-(trifluoromethoxy) phenyl)-6-methyl the synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 27-(1) and 18-(2), title compound (101mg, 0.217mmol) be obtained from the compound (370mg obtained in production instance 19,1.02mmol) and the compound (125mg, 0.511mmol) obtained in the production instance 8-(3).
1H-NMR(400MHz,CDCl3)δ(ppm):1.23(d,J＝6.6Hz,3H),2.97(ddd,J＝2.7,10.5,16.0Hz,1H),3.07(ddd,J＝1.2,3.9,16.0Hz,1H),3.40(s,3H),3.61(ddd,J＝1.6,10.5,12.5Hz,1H),3.67-3.79(m,1H),3.94(dd,J＝8.4,14.6Hz,1H),4.14-4.27(m,2H),4.63-4.73(m,2H),4.74(s,2H),7.28-7.37(m,1H),7.43(dd,J＝2.3,8.6Hz,1H),7.67(d,J＝2.0Hz,1H)。
ESI-MS m/z 465,467[M+H]+487,489[M+Na]+
(2) (R)-3-(3-((methoxymethoxy) methyl)-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2- picoline-4-base) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 1-(5), title compound (46.8mg, 0.098mmol) be obtained from the compound (50.0mg obtained in example 39-(1), 0.107mmol) with 2-picoline-4-boric acid (29.4mg, 0.215mmol).
ESI-MS m/z 478[M+H]+
(3) (R)-(5-(6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene-3-base)-2-(trifluoromethoxy) phenyl) synthesis of methyl alcohol
The compound (46.8mg, 0.098mmol) obtained in example 39-(2) and the solution of CSA (68.3mg, 0.294mmol) in methyl alcohol (1.0mL) are carried out stirring and heats 4 hours under reflux.This reaction mixture is cooled to room temperature, adds TEA (0.1mL), and then this mixture is under reduced pressure concentrated.The resistates of this generation is filtered by a kind of silicagel pad (NH silica gel) and then under reduced pressure this elutriant is concentrated.The resistates of this generation is carried out purifying, to obtain title compound (25.2mg, 0.058mmol) by NH silicon thin-layer chromatography (ethyl acetate).
1H-NMR(400MHz,CDCl3)δ(ppm):1.26(d,J＝6.6Hz,3H),2.59(s,3H),3.20(ddd,J＝2.3,10.5,16.4Hz,1H),3.36(dd,J＝3.9,15.6,1H),3.59-3.73(m,1H),3.74-3.87(m,1H),4.00(dd,J＝8.6,14.8Hz,1H),4.18-4.32(m,2H),4.80(s,2H),7.29-7.38(m,2H),7.43-7.52(m,2H),7.77(d,J＝2.3Hz,1H),8.49(d,J＝4.7Hz,1H)。
ESI-MS m/z 434[M+H]+
(4) (R)-3-(3-(methyl fluoride)-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4- base) synthesis of-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
Under ice-cooling, to the compound (21.3mg obtained in example 39-(3) in DCM (1.0mL), 0.049mmol) and in the solution of TEA (69 μ L, 0.50mmol) add DAST (0.033mL, 0.25mmol).This reaction soln is heated to room temperature, stirs 20 hours, and then filtered by a kind of silicagel pad (NH silica gel).The solution of this generation is under reduced pressure concentrated and is used by resistates silicon thin-layer chromatography (ethyl acetate) and NH silicon thin-layer chromatography (normal heptane/ethyl acetate) to carry out purifying continuously, to obtain title compound (3.0mg, 0.0069mmol).
1H-NMR(400MHz,CDCl3)δ(ppm):1.28(d,J＝6.6Hz,3H),2.59(s,3H),3.21(ddd,J＝2.3,10.5,16.0Hz,1H),3.37(dd,J＝4.3,16.0Hz,1H),3.68(t,J＝11.1Hz,1H),3.76-3.87(m,1H),4.03(dd,J＝8.6,14.8Hz,1H),4.19-4.28(m,2H),5.55(d,J＝46.9Hz,2H),7.29(dd,J＝1.4,5.3Hz,1H),7.37-7.43(m,1H),7.45(s,1H),7.58(dd,J＝1.8,8.4Hz,1H),7.71(d,J＝2.0Hz,1H),8.50(d,J＝5.1Hz,1H)。
ESI-MS m/z 436[M+H]+
Example 40
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-(methyl fluoride)-1-(2-picoline-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 39-(2), title compound (18mg, 0.043mmol) is obtained from the compound (28mg, 0.069mmol) obtained in example 27-(2).
1H-NMR(400MHz,CDCl3)δ(ppm):2.35(s,3H),2.59(s,3H),3.22(ddd,J＝2.3,10.9,16.0Hz,1H),3.41(dd,J＝3.7,16.2Hz,1H),3.66-3.75(m,1H),3.83-3.95(m,1H),4.06(dd,J＝8.6,14.8Hz,1H),4.28-4.46(m,2H),4.55(ddd,J＝4.7,9.8,46.1Hz,1H),4.56(d,J＝14.8Hz,1H),6.57(t,J＝73.4Hz,1H),7.19(d,J＝8.2Hz,1H),7.29(dd,J＝1.4,4.9Hz,1H),7.33(dd,J＝2.3,8.6Hz,1H),7.45-7.48(m,2H),8.50(d,J＝5.1Hz,1H)。
ESI-MS m/z 418[M+H]+
Example 41
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-1-(2-picoline-4-base)- the synthesis of 5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene
According to the method for example 39-(2), title compound (13mg, 0.030mmol) is obtained from the compound (26mg, 0.061mmol) obtained in example 29-(2).
1H-NMR(400MHz,CDCl3)δ(ppm):2.60(s,3H)3.19-3.29(m,1H)3.42(dd,J＝4.3,16.4Hz,1H),3.72(t,J＝11.9Hz,1H),3.86-4.00(m,4H)4.08(dd,J＝9.0,14.8Hz,1H),4.28-4.47(m,2H),4.48-4.66(m,2H),7.11(d,J＝8.2Hz,1H),7.26(d,J＝4.7Hz,1H),7.30(d,J＝5.1Hz,1H),7.46(s,1H),7.68(d,J＝8.2Hz,1H),8.52(d,J＝5.1Hz,1H)。
ESI-MS m/z 436[M+H]+
Each each compound described in table 1 to table 7 synthesizes according to one or more methods of any example described above.
[table 1]
[table 2]
[table 3]
[table 4]
[table 5]
[table 6]
[table 7]
Example R R 1 R 2 R 3 R 4 ESI-MS
Numbering [M+H] +
236 CH 3 OCHF 2 CH 2F H CH 3 418
237 CH 3 OCHF 2 CH 2OH H CH 3 416
238 CH 3 Cl CH 2F CH 3 CH 3 400
239 CH 3 OCH 2CH 2F Cl CH 3 CH 3 430
240 CH 3 CF 2CH 3 OCH 3 H CH 3 414
241 CH 3 OCH 2CH 3 CH 3 CH 3 CH 3 392
242 CH 3 OCH(CH 3) 2 CH 3 CH 3 CH 3 406
243 CH 2F OCH 2CH 3 CH 3 CH 3 CH 3 410
244 CH 2F OCH(CH 3) 2 CH 3 CH 3 CH 3 424
245 CH 2F OCH 3 CH 3 CH 3 CH 3 396
Test example 1: to the affinity of mGluR2
(preparation of the cellular membrane fractions of the HEK293 cell of stably express people mglur 2 (mGluR2))
At 37 DEG C at 5%CO 2under, by the HEK293 cell cultures of stably express mankind mGluR2 and mankind's glutamate transporter SLC1A3 (penicillin of 50 units/mL in Da Erbai kirschner improvement eagle substratum (Dulbecco's modified Eagle's medium) with 10% foetal calf serum, the Streptomycin sulphate of 50 μ g/mL, the Geneticin of 60 μ g/mL, the hygromycin B of 400 μ g/mL and the glutamine of 2mM).The cell culture PBS (-) merged is washed twice, and then to wipe off with cell scraper, and stand centrifugation 5 minutes for collecting cell at 4 DEG C and 1500rpm.Centrifugal throw out (cell precipitation thing) is carried out homogenizing in the 20mM HEPES damping fluid (pH 7.4) comprising 10mM EDTA and stands centrifugal 30 minutes at 4 DEG C and 1500x g.This supernatant liquor (fraction of dissolving) is stood centrifugation 30 minutes at 4 DEG C and 40,000x g, and therefore, gathers in the crops undissolved fraction.After by the fraction of 20mM HEPES damping fluid (pH 7.4) additionally this acquisition of centrifuge washing comprising 10mM EDTA, this throw out 20mM HEPES damping fluid comprising 0.1mM EDTA is carried out centrifugal suspension, and by obtaining cellular membrane fractions at 4 DEG C and 40,000x g centrifugation 30 minutes.Being suspended in the protein concn of 3mg/mL by the cellular membrane fractions gathered in the crops thus comprises in the 20mM HEPES damping fluid of 0.1mM EDTA, by it-80 DEG C of storages.
([ 35s] GTP γ S combines mensuration)
The Frozen cells film fraction prepared as described above is thawed before the use, and is used by this resultant damping fluid dilution to measure (final concentration: 20mM HEPES, 100mM NaCl, 1mM MgCl for combination 2, 3 μMs of GDP, 300 μ g/mL saponin(es, 0.1%BSA).Add the compound of each example to the cellular membrane fractions comprising 1.8 μ g to 3 μ g/ mensuration membranins on plate, at room temperature hatch 30 minutes subsequently.After this, L-glutamic acid (final concentrations with 10 μMs) is added to it, at room temperature hatches 15 minutes, and after this, to its add [ 35s] GTP γ S (final concentration with 0.8kBq) and 588 μ g WGA-SPA pearls, at room temperature hatch 1 hour subsequently.After hatching, this plate is stood centrifugation under 2,500rpm and room temperature, and then, use enzyme report analysis instrument to measure theca cell in conjunction with radioactivity.
By implement under the disappearance of L-glutamic acid above describe reaction acquisition [ 35s] GTP γ S binding capacity is defined as non-specific binding, and with exist at L-glutamic acid under obtain [ 35s] different definition of GTP γ S binding capacity is specific binding.Different concns place based on the compound at each example suppresses the ratio of specific binding, obtains suppression curve.Based on these suppress curve calculation specificitys [ 35s] GTP γ S binding capacity suppressed 50% (IC50 value) time each example compound concentration and be presented in table 8 and table 9.
[table 8]
[table 9]
Test example 2: novel object identification (NOR) test in rat
Six weeks large Male Long-Evans rats are used to be used for this test.Start this test a few days ago, make these rats adapt to experimental implementation, such as administration and test set (that is, the 40cm of a kind of black or grey is wide, the plastic cages that 30cm is dark and 45cm is high).Each test compounds is dissolved in the hydrochloric acid of 0.1N, gives for oral.After administration 30 minutes, carry out the Intraperitoneal medication of scopolamine hydrobromide with the dosage of 0.3mg/kg, to induce cognitive impairment.Another are after 30 minutes, each rat is adapted to 3 minutes in this test set, and after this, two obstacles (block) being in same shape be placed on as acquistion test (acquisition trial) in this test set, the exploration time measurement for each obstacle is 5 minutes.Latter two hour is tested in this acquistion, this rat is adapted to 3 minutes in this test set, and after this, by with test in this acquistion in those identical obstacles used and there is difform new obstacle be placed in cage and be used for memory test (retention trial).Exploration time measurement for each obstacle is 3 minutes, and the ratio of the new exploration time of obstacle of use and the summation of the exploration time of each obstacle is calculated as index of discrimination.By the index of discrimination so obtained and to compare below: the one group of rat giving separately matrix (matrix group), give separately one group of rat of Scopolamine (independent Scopolamine group), and give one group of rat of test compounds and Scopolamine, to assess the effect of this test compounds to the novel object identification function (cognitive function) of rat.
Each index of discrimination is shown as mean value and standard deviation.Analyzed by independent t-inspection in matrix group and the statistical significance separately between Scopolamine group.Statistical significance between independent Scopolamine group and each sample sets is by One-way ANOVA and then analyzed by Dunnett's multiple comparative test.In both sides, significance level is set to 5%.If the index of discrimination separately in Scopolamine group, significantly lower than the index of discrimination in matrix group, it is well established that cognitive impairment is fully induced, and therefore, assesses this test compounds in corresponding group.This analysis is carried out by using the Prism 5 of the Windows being used for Japanese version 5.03.
Standing the group of the cognitive impairment of being induced by Scopolamine and using the minimum effective dose finding statistically significant difference between the group of each compound treatment to show in table 10.
[table 10]
* statistically significant difference is not found at this proof load.
industrial applicibility
As described above, imidazolidine of the present invention also [1,5-d] [Isosorbide-5-Nitrae] oxygen azepine derivate or its pharmaceutically acceptable acid salt be a kind of antagonist for group II metabotropic glutamate receptor and show a kind of effect suppressing the downstream signal of mGluR2.In addition, compound of the present invention shows the effect improving novel object identification function in the rat of standing the cognitive impairment of being induced by Scopolamine.Correspondingly, compound of the present invention is used for the neurological disorder relevant to glutaminate dysfunction as therapeutical agent and the disease that relates to mGluR2 (that is, the hypotype of these metabotropic receptors) is applicable, such as alzheimer's disease.

Claims (20)

1. the compound represented by following chemical formula (I) or its pharmaceutical acceptable acid additive salt:
Wherein R is hydrogen atom or optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl, wherein
When R is hydrogen atom,
R 1be chlorine atom, bromine atoms, trifluoromethyl, ethyl, trifluoromethoxy, the methoxyl group be substituted by phenyl, by C 3-8the methoxyl group of cycloalkyl substituted, the oxyethyl group optionally replaced by 1 to 3 fluorine atom or C 3-8cycloalkyloxy,
R 2fluorine atom, chlorine atom, the methyl optionally replaced by 2 to 3 fluorine atoms, the methoxyl group optionally replaced by 1 to 3 fluorine atom or optionally by the oxyethyl group that 1 to 3 fluorine atom replaces,
R 3hydrogen atom or methyl, and
R 4fluorine atom or optionally by the methyl that 1 to 3 fluorine atom replaces, or
When R is optionally by the C of 1 to 3 fluorine atom replacement 1-6during alkyl,
R 1be hydrogen atom, halogen atom, optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl, is optionally selected from fluorine atom and C by 1 to 3 3-8the C that substituting group in cycloalkyl replaces 1-6alkoxyl group, C 3-8cycloalkyloxy, or 4-to 6-unit heterocyclylalkoxy groups,
R 2be hydrogen atom, cyano group, halogen atom, is optionally selected from the C of the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or be optionally selected from fluorine atom, C by 1 to 3 3-8cycloalkyl and 4-to 6-unit Heterocyclylalkyl in substituting group replace C 1-6alkoxyl group,
R 3hydrogen atom or C 1-6alkyl, and
R 4the C being optionally selected from the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or C 1-6alkoxyl group.
2. compound according to claim 1 or its pharmaceutically acceptable acid salt, wherein
R is optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl,
R 1be hydrogen atom, halogen atom, optionally by the C of 1 to 3 fluorine atom replacement 1-6alkyl, is optionally selected from fluorine atom and C by 1 to 3 3-8the C that substituting group in cycloalkyl replaces 1-6alkoxyl group, C 3-8cycloalkyloxy, or 4-to 6-unit heterocyclylalkoxy groups,
R 2be hydrogen atom, cyano group, halogen atom, is optionally selected from the C of the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or be optionally selected from fluorine atom, C by 1 to 3 3-8cycloalkyl and 4-to 6-unit Heterocyclylalkyl in substituting group replace C 1-6alkoxyl group,
R 3hydrogen atom or C 1-6alkyl, and
R 4the C being optionally selected from the substituting group replacement in fluorine atom and hydroxyl by 1 to 3 1-6alkyl, or C 1-6alkoxyl group.
3. compound according to claim 2 or its pharmaceutically acceptable acid salt, wherein R is methyl, ethyl, methyl fluoride or difluoromethyl.
4. compound according to claim 3 or its pharmaceutically acceptable acid salt,
Wherein R 1hydrogen atom, fluorine atom, chlorine atom, methyl, methyl fluoride, difluoromethyl, trifluoromethyl, ethyl, 1,1-bis-fluoro ethyl, methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, 2-fluorine oxyethyl group, 2-propoxy-, cyclo propyl methoxy, ring propoxy-or (trimethylene oxide-3-base) oxygen base.
5. compound according to claim 4 or its pharmaceutically acceptable acid salt,
Wherein R 2hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, methyl fluoride, difluoromethyl, trifluoromethyl, methylol, ethyl, methoxyl group, fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group, 2-fluorine oxyethyl group, 2-propoxy-, cyclo propyl methoxy, cyclobutyl methoxyl group or (tetrahydrochysene-2H-pyrans-4-base) methoxyl group.
6. compound according to claim 5 or its pharmaceutically acceptable acid salt, wherein R 3hydrogen atom or methyl.
7. compound according to claim 6 or its pharmaceutically acceptable acid salt, wherein R 4methyl, methyl fluoride, difluoromethyl, methylol or methoxyl group.
8. compound according to claim 2 or its pharmaceutically acceptable acid salt, wherein
R is optionally by the methyl that 1 to 2 fluorine atom replaces,
R 1be hydrogen atom, chlorine atom, optionally by the methyl that 1 to 3 fluorine atom replaces, ethyl, optionally by the C of 1 to 3 fluorine atom replacement 1-6alkoxyl group, or C 3-6cycloalkyloxy,
R 2be cyano group, chlorine atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl or optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group,
R 3hydrogen atom or methyl, and
R 4optionally by the methyl of 1 to 3 fluorine atom replacement.
9. compound according to claim 2 or its pharmaceutically acceptable acid salt, wherein
R is optionally by the methyl that 1 to 2 fluorine atom replaces,
R 1be hydrogen atom, halogen atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl, optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group or C 3-6cycloalkyloxy,
R 2be cyano group, halogen atom, optionally by C that 1 to 3 fluorine atom replaces 1-6alkyl or optionally by C that 1 to 3 fluorine atom replaces 1-6alkoxyl group,
R 3methyl, and
R 4that its condition is optionally by the methyl that 1 to 3 fluorine atom replaces
Work as R 1when being unsubstituted methoxyl group, R 2it not fluorine atom.
10. one kind is selected from compound or its pharmaceutically acceptable acid salt of following compound:
(R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-6-methyl-3-(3-methyl-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-chloro-4-ring propoxyphenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-ring propoxy--3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(3-chloro-4-methoxy phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(the chloro-4-ethoxyl phenenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(the chloro-4-isopropyl phenyl of 3-)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(R)-3-(3-(methyl fluoride)-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene,
(S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-6-(methyl fluoride)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, and
(S)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-1-(2-picoline-4-base)-5,6,8,9-imidazolidines also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene.
11. (R)-3-(the chloro-3-p-methoxy-phenyl of 4-)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, is represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
12. (R)-1-(2,6-lutidine-4-base)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, is represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
13. (R)-3-(3-methoxyl group-4-(trifluoromethoxy) phenyl)-6-methyl isophthalic acid-(2-picoline-4-base)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
14. (R)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, is represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
15. (R)-3-(the chloro-4-of 3-(difluoro-methoxy) phenyl)-1-(2,6-lutidine-4-base)-6-methyl-5,6,8,9-imidazolidine is [1,5-d] [1 also, 4] oxygen azatropylidene, is represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
16. (S)-3-(4-(difluoro-methoxy)-3-aminomethyl phenyl)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
17. (S)-1-(2,6-lutidine-4-base)-6-(methyl fluoride)-3-(3-methoxyl group-4-(trifluoromethyl) phenyl)-5,6,8,9-imidazolidine also [1,5-d] [Isosorbide-5-Nitrae] oxygen azatropylidene, represented by following chemical formula:
Or its pharmaceutically acceptable acid salt.
18. 1 kinds of medicinal compositionss, comprise compound according to any one of claim 1-17 or pharmaceutically acceptable acid salt and one or more pharmaceutically acceptable vehicle.
19. medicinal compositionss according to claim 18, it is effective disease or symptom for the antagonistic action of group II metabotropic glutamate receptor wherein that this medicinal compositions is used for the treatment of.
20. medicinal compositionss according to claim 19, wherein this disease or symptom are alzheimer's diseases.
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